Pub Date : 2025-11-07DOI: 10.1038/s41375-025-02794-1
K. S. Kurz, A. Zamo, C. Drewes, E. Madej, C. Laurent, B. Burroni, M. Donzel, L. Xerri, L. Mescam, L. Plank, L. M. R. Gjerdrum, J. Geyer, J. Richter, I. Oschlies, W. Klapper, S. Gramlich, J. Doll, S. Roth, K. Maurus, A. M. Staiger, R. Siebert, M-Q. Du, A. Rosenwald, G. Ott, H. Horn
Rearrangement of Cyclin D1 (CCND1-R) is the hallmark genetic lesion of mantle cell lymphoma (MCL). However, recently diffuse large B-cell lymphomas (DLBCL) have been described carrying a CCND1-R, often with additional rearrangements of BCL2, BCL6 and/or MYC raising the question if these are bona fide DLBCL or pleomorphic MCL. Protein expression and fluorescence in situ hybridisation (FISH) screening of 708 aggressive B-cell lymphomas failed to disclose CCND1-R, demonstrating the rarity of such cases. Fifteen large B-cell tumours, with CCND1-R were collected from different institutions and characterized by immunohistochemistry and for their molecular features. Three of 15 cases were CD5 positive, and all cases were negative for SOX11 but exhibited cyclin D1 staining and CCND1-R by FISH. In 10/15 cases IG could be determined as rearrangement partner by FISH or WGS with occurrence of both aberrant VDJ rearrangement and IGH class-switch recombination (CSR). Eight of 15 tumours had additional translocations involving MYC, BCL2, or BCL6. 8/12 evaluable cases showed significantly mutated IGHV genes and evidence of intraclonal variations in their rearranged IGHV genes. WES disclosed a mutational spectrum typical of DLBCL in 14/14 evaluable cases. We conclude that DLBCL CCND1-R do exist and that CCND1-R in DLBCL can occur without additional translocations.
{"title":"Cyclin D1 rearranged diffuse large B-cell lymphoma—an evolving concept","authors":"K. S. Kurz, A. Zamo, C. Drewes, E. Madej, C. Laurent, B. Burroni, M. Donzel, L. Xerri, L. Mescam, L. Plank, L. M. R. Gjerdrum, J. Geyer, J. Richter, I. Oschlies, W. Klapper, S. Gramlich, J. Doll, S. Roth, K. Maurus, A. M. Staiger, R. Siebert, M-Q. Du, A. Rosenwald, G. Ott, H. Horn","doi":"10.1038/s41375-025-02794-1","DOIUrl":"10.1038/s41375-025-02794-1","url":null,"abstract":"Rearrangement of Cyclin D1 (CCND1-R) is the hallmark genetic lesion of mantle cell lymphoma (MCL). However, recently diffuse large B-cell lymphomas (DLBCL) have been described carrying a CCND1-R, often with additional rearrangements of BCL2, BCL6 and/or MYC raising the question if these are bona fide DLBCL or pleomorphic MCL. Protein expression and fluorescence in situ hybridisation (FISH) screening of 708 aggressive B-cell lymphomas failed to disclose CCND1-R, demonstrating the rarity of such cases. Fifteen large B-cell tumours, with CCND1-R were collected from different institutions and characterized by immunohistochemistry and for their molecular features. Three of 15 cases were CD5 positive, and all cases were negative for SOX11 but exhibited cyclin D1 staining and CCND1-R by FISH. In 10/15 cases IG could be determined as rearrangement partner by FISH or WGS with occurrence of both aberrant VDJ rearrangement and IGH class-switch recombination (CSR). Eight of 15 tumours had additional translocations involving MYC, BCL2, or BCL6. 8/12 evaluable cases showed significantly mutated IGHV genes and evidence of intraclonal variations in their rearranged IGHV genes. WES disclosed a mutational spectrum typical of DLBCL in 14/14 evaluable cases. We conclude that DLBCL CCND1-R do exist and that CCND1-R in DLBCL can occur without additional translocations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2988-2996"},"PeriodicalIF":13.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02794-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455513","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}
Pub Date : 2025-11-07DOI: 10.1038/s41375-025-02795-0
Riccardo Moia, Simone Ragaini, Luciano Cascione, Andrea Rinaldi, Elisa Genuardi, Donatella Talotta, Mohammad Almasri, Alessio Bruscaggin, Gian Maria Zaccaria, Andrea Evangelista, Aurora Maria Civita, Alice Di Rocco, Luigi Petrucci, Federica Cavallo, Melania Celli, Mario Luppi, Caterina Stelitano, Piero Maria Stefani, Carlo Visco, Atto Billio, Ivana Casaroli, Claudia Castellino, Enzo Pavone, Sara Galimberti, Caterina Plenteda, Francesco Merli, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Marco Ladetto, Francesco Bertoni, Simone Ferrero
{"title":"The integration of gene mutations and copy number variations refines the prognosis of mantle cell lymphoma: long-term results of the Fondazione Italiana Linfomi MCL0208 clinical trial","authors":"Riccardo Moia, Simone Ragaini, Luciano Cascione, Andrea Rinaldi, Elisa Genuardi, Donatella Talotta, Mohammad Almasri, Alessio Bruscaggin, Gian Maria Zaccaria, Andrea Evangelista, Aurora Maria Civita, Alice Di Rocco, Luigi Petrucci, Federica Cavallo, Melania Celli, Mario Luppi, Caterina Stelitano, Piero Maria Stefani, Carlo Visco, Atto Billio, Ivana Casaroli, Claudia Castellino, Enzo Pavone, Sara Galimberti, Caterina Plenteda, Francesco Merli, Abdurraouf Mokhtar Mahmoud, Davide Rossi, Gianluca Gaidano, Marco Ladetto, Francesco Bertoni, Simone Ferrero","doi":"10.1038/s41375-025-02795-0","DOIUrl":"10.1038/s41375-025-02795-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"219-223"},"PeriodicalIF":13.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02795-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145455413","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}
Pub Date : 2025-11-03DOI: 10.1038/s41375-025-02790-5
Lingge Tu, Fangfang He, Jun Mun Liew, Chun-Fung Sin, Lichuan Zheng, Sze-Pui Tsui, Xinyu Miao, Hoi-yi Chan, Alvin Chun Hang Ma, Wenqing Zhang, Yiyue Zhang, Anskar Y. H. Leung, Xuan Sun
{"title":"asxl1 C-terminal truncation and SRSF2 mutation drive leukemogenesis via immune reprogramming","authors":"Lingge Tu, Fangfang He, Jun Mun Liew, Chun-Fung Sin, Lichuan Zheng, Sze-Pui Tsui, Xinyu Miao, Hoi-yi Chan, Alvin Chun Hang Ma, Wenqing Zhang, Yiyue Zhang, Anskar Y. H. Leung, Xuan Sun","doi":"10.1038/s41375-025-02790-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02790-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427425","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}
Pub Date : 2025-11-03DOI: 10.1038/s41375-025-02793-2
Alessandra Tedeschi, Anna Maria Frustaci, Pierantonio Menna, Giorgio Minotti
{"title":"Correction: Fixed-duration therapy of chronic lymphocytic leukemia with venetoclax and Bruton tyrosine kinase inhibitors: an insight into differences between ibrutinib and acalabrutinib","authors":"Alessandra Tedeschi, Anna Maria Frustaci, Pierantonio Menna, Giorgio Minotti","doi":"10.1038/s41375-025-02793-2","DOIUrl":"10.1038/s41375-025-02793-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"3060-3060"},"PeriodicalIF":13.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02793-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427427","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}
Pub Date : 2025-11-03DOI: 10.1038/s41375-025-02787-0
Mouhamad Khouja, Elisa Genuardi, Simone Ferrero, Anna Laqua, Beatrice Alessandria, Onno J. H. M. Verhagen, Christa H. E. Homburg, Ramón García Sanz, Alejandro Medina Herrera, Vincent H. J. van der Velden, Maria Gomes da Silva, Paula Gameiro, Jeanette Doorduijn, Eva Giné, Carlo Visco, Monika Brüggemann, Claudia D. Baldus, Marco Ladetto, Christian Schmidt, Martin Dreyling, Linmiao Jiang, Eva Hoster, Nikos Darzentas, Karol Pal, Guranda Chitadze, James Peter Stewart, David Gonzalez, Christiane Pott, on behalf of the European MCL Network
Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.
{"title":"Noninvasive genotyping and early disease dynamics demonstrate the efficacy of ibrutinib in combination with immunochemotherapy in patients with mantle cell lymphoma treated in the TRIANGLE trial","authors":"Mouhamad Khouja, Elisa Genuardi, Simone Ferrero, Anna Laqua, Beatrice Alessandria, Onno J. H. M. Verhagen, Christa H. E. Homburg, Ramón García Sanz, Alejandro Medina Herrera, Vincent H. J. van der Velden, Maria Gomes da Silva, Paula Gameiro, Jeanette Doorduijn, Eva Giné, Carlo Visco, Monika Brüggemann, Claudia D. Baldus, Marco Ladetto, Christian Schmidt, Martin Dreyling, Linmiao Jiang, Eva Hoster, Nikos Darzentas, Karol Pal, Guranda Chitadze, James Peter Stewart, David Gonzalez, Christiane Pott, on behalf of the European MCL Network","doi":"10.1038/s41375-025-02787-0","DOIUrl":"10.1038/s41375-025-02787-0","url":null,"abstract":"Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"95-105"},"PeriodicalIF":13.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02787-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433891","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}
Pub Date : 2025-10-27DOI: 10.1038/s41375-025-02791-4
T. Benz, P. Larghero, C. Meyer, T. Hanewald, D. Brüggmann, A.-E. Hentrich, F. Louwen, R. Marschalek
The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.
{"title":"CRISPR/Cas9-mediated t(4;11) translocation in human hematopoietic stem/precursor cells demonstrates plasticity to differentiate into either the myeloid or lymphoid lineage","authors":"T. Benz, P. Larghero, C. Meyer, T. Hanewald, D. Brüggmann, A.-E. Hentrich, F. Louwen, R. Marschalek","doi":"10.1038/s41375-025-02791-4","DOIUrl":"10.1038/s41375-025-02791-4","url":null,"abstract":"The chromosomal translocation t(4;11)(q21;q23) is frequently diagnosed in KMT2A-r Acute Leukemia patients. Although we understand much about the function of both wildtype KMT2A and AFF1 multiprotein complexes, little is known about the molecular actions the two fusion proteins KMT2A::AFF1 and AFF1::KMT2A during the very early steps of disease onset and progression. Most published data have been generated in t(4;11) cell lines or transplanted mouse models, where exactly this process remains a black box. Here, we present the results of our efforts to establish a t(4;11) chromosomal translocation in human hematopoietic stem/precursor cells by CRISPR/Cas9. These genetically modified cells can be expanded over 5-6 months in vitro and their potential to differentiate was examined with IL-7 supplementation. The benefit of this model system is that (1) both reciprocal fusion proteins are concomitantly present, and (2) a molecular surveillance is possible at any timepoint through analysis of RNA, DNA or protein. Thus, the CRISPR/Cas9 technique allowed us to create a bona fide model system to study the very early steps of leukemia onset at the molecular level. In conclusion, this approach is the fastest way to investigate and characterize KMT2A-r fusions in primary human cells.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"72-86"},"PeriodicalIF":13.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02791-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373959","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}
Pub Date : 2025-10-27DOI: 10.1038/s41375-025-02764-7
Jochen Greiner, Patrick J. Schuler, Hubert Schrezenmeier, Johanna Weiss, Christiane Bulach, Marlies Goetz, Barbara-ann Guinn
Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukemia (AML). Despite being shown to be effective in the context of stem cell transplants for almost 50 years, further improvements are required to prevent relapse and its associated morbidity. The therapeutic use of immune checkpoint inhibition in AML is still under debate. We have shown some positive effects of it on cancer control ex vivo. We found that anti-programmed death-1 (PD-1) antibodies in combination with azacitidine (AZA) had the most pronounced effect on T-cell activation and control of leukemic progenitor/stem cell growth. We identified which leukemia-associated antigen (LAA) stimulated the largest IFNγ immune response by T cells from AML patients with and without the nucleophosmin 1 (NPM1) mutation and which immunotherapeutic strategy, either alone or in combination with the immune checkpoint anti-PD-1, could enhance immune responses against leukemic cells. Anti-PD-1 with AZA had a particularly strong effect with a mean colony reduction of 56%. Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells but also leukemic progenitor/stem cells. The combination of LAA-peptides with anti-PD-1 antibody and one further immunotherapeutic could be an interesting option for further clinical studies.
{"title":"Different immunotherapeutic combinations enhance specific T cell immune responses against leukemic cells, as well as leukemic progenitor cells, in acute myeloid leukemia","authors":"Jochen Greiner, Patrick J. Schuler, Hubert Schrezenmeier, Johanna Weiss, Christiane Bulach, Marlies Goetz, Barbara-ann Guinn","doi":"10.1038/s41375-025-02764-7","DOIUrl":"10.1038/s41375-025-02764-7","url":null,"abstract":"Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukemia (AML). Despite being shown to be effective in the context of stem cell transplants for almost 50 years, further improvements are required to prevent relapse and its associated morbidity. The therapeutic use of immune checkpoint inhibition in AML is still under debate. We have shown some positive effects of it on cancer control ex vivo. We found that anti-programmed death-1 (PD-1) antibodies in combination with azacitidine (AZA) had the most pronounced effect on T-cell activation and control of leukemic progenitor/stem cell growth. We identified which leukemia-associated antigen (LAA) stimulated the largest IFNγ immune response by T cells from AML patients with and without the nucleophosmin 1 (NPM1) mutation and which immunotherapeutic strategy, either alone or in combination with the immune checkpoint anti-PD-1, could enhance immune responses against leukemic cells. Anti-PD-1 with AZA had a particularly strong effect with a mean colony reduction of 56%. Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells but also leukemic progenitor/stem cells. The combination of LAA-peptides with anti-PD-1 antibody and one further immunotherapeutic could be an interesting option for further clinical studies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"130-137"},"PeriodicalIF":13.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02764-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373958","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}
Pub Date : 2025-10-27DOI: 10.1038/s41375-025-02781-6
Marius Bill, Jan-Niklas Eckardt, Konstanze Döhner, Maximillian-Alexander Röhnert, Christian Rausch, Klaus H. Metzeler, Karsten Spiekermann, Sebastian Stasik, Alexander A. Wurm, Tim Sauer, Sebastian Scholl, Ulf Schnetzke, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Utz Krug, Bernhard Wörmann, Hermann Einsele, Wolfgang Hiddemann, Dennis Görlich, Cristina Sauerland, Björn Steffen, Andreas Neubauer, Andreas Burchert, Kerstin Schäfer-Eckart, Wolfgang E. Berdel, Christoph Schliemann, Stefan W. Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Johannes Schetelig, Jan Moritz Middeke, Lars Bullinger, Michael Heuser, Felicitas Thol, Hubert Serve, Claudia D. Baldus, Uwe Platzbecker, Carsten Müller-Tidow, Jan Válka, Jiří Šrámek, Barbora Weinbergerova, Jiri Mayer, Pierre-Yves Dumas, Sarah Bertoli, Eric Delabesse, Christian Récher, Arnaud Pigneux, Tobias Herold, Arnold Ganser, Hartmut Döhner, Martin Bornhäuser, Christian Thiede, Christoph Röllig
In the European LeukemiaNet (ELN) 2022 recommendations, myelodysplasia-related (MR) gene mutations were classified as a novel adverse prognostic category for intensively treated acute myeloid leukemia (AML). To assess the prognostic impact of individual MR genes within the ELN, clinical, cytogenetic, and molecular data from 4,978 intensively treated AML patients were analyzed. Remission rates and survival outcomes were evaluated. For analyses in context of ELN2022 classification, patients carrying an MR mutation were excluded from the adverse group and analyzed separately; those with co-occurring favorable or intermediate features remained in their respective groups. Overall, 1698 patients (34.1%) harbored at least one MR mutation. Lower complete remission rates were observed in MR-mutated cases (65.7% vs 77.7%; p < 0.001) along with shorter event-free (HR 1.45; p < 0.001), relapse-free (HR 1.33; p < 0.001), and overall survival (HR 1.45; p < 0.001) were recorded. Gene-specific prognostic patterns emerged: ASXL1, RUNX1, SF3B1, and U2AF1 mutations associated with adverse risk-like outcomes; SRSF2 and STAG2 aligned with intermediate-risk; BCOR, EZH2, and ZRSR2 did not differ significantly from intermediate or adverse risk. These findings from a large cooperative cohort highlight prognostic heterogeneity among MR mutations and suggest that SRSF2 and STAG2 mutations are associated with less adverse risk patterns, comparable to intermediate-risk.
在欧洲白血病网（ELN） 2022推荐中，骨髓增生异常相关（MR）基因突变被列为强化治疗的急性髓性白血病（AML）的一种新的不良预后类别。为了评估ELN内单个MR基因对预后的影响，分析了4978名强化治疗的AML患者的临床、细胞遗传学和分子数据。评估缓解率和生存结果。在ELN2022分类的背景下进行分析时，携带MR突变的患者被排除在不良组之外，并单独分析；那些同时出现有利或中间特征的人留在各自的组中。总体而言，1698例患者（34.1%）至少有一种MR突变。mr突变病例的完全缓解率较低（65.7% vs 77.7%, p < 0.001），无事件（HR 1.45, p < 0.001）、无复发（HR 1.33, p < 0.001）和总生存期较短（HR 1.45, p < 0.001）。基因特异性预后模式出现：ASXL1、RUNX1、SF3B1和U2AF1突变与不良风险样结果相关；SRSF2和STAG2为中等风险；BCOR、EZH2和ZRSR2与中度或不良风险无显著差异。这些来自大型合作队列的研究结果突出了MR突变之间的预后异质性，并表明SRSF2和STAG2突变与较少的不良风险模式相关，与中等风险相当。
{"title":"Differential prognostic impact of myelodysplasia-related gene mutations in a European cohort of 4978 intensively treated AML patients","authors":"Marius Bill, Jan-Niklas Eckardt, Konstanze Döhner, Maximillian-Alexander Röhnert, Christian Rausch, Klaus H. Metzeler, Karsten Spiekermann, Sebastian Stasik, Alexander A. Wurm, Tim Sauer, Sebastian Scholl, Ulf Schnetzke, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Utz Krug, Bernhard Wörmann, Hermann Einsele, Wolfgang Hiddemann, Dennis Görlich, Cristina Sauerland, Björn Steffen, Andreas Neubauer, Andreas Burchert, Kerstin Schäfer-Eckart, Wolfgang E. Berdel, Christoph Schliemann, Stefan W. Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Johannes Schetelig, Jan Moritz Middeke, Lars Bullinger, Michael Heuser, Felicitas Thol, Hubert Serve, Claudia D. Baldus, Uwe Platzbecker, Carsten Müller-Tidow, Jan Válka, Jiří Šrámek, Barbora Weinbergerova, Jiri Mayer, Pierre-Yves Dumas, Sarah Bertoli, Eric Delabesse, Christian Récher, Arnaud Pigneux, Tobias Herold, Arnold Ganser, Hartmut Döhner, Martin Bornhäuser, Christian Thiede, Christoph Röllig","doi":"10.1038/s41375-025-02781-6","DOIUrl":"10.1038/s41375-025-02781-6","url":null,"abstract":"In the European LeukemiaNet (ELN) 2022 recommendations, myelodysplasia-related (MR) gene mutations were classified as a novel adverse prognostic category for intensively treated acute myeloid leukemia (AML). To assess the prognostic impact of individual MR genes within the ELN, clinical, cytogenetic, and molecular data from 4,978 intensively treated AML patients were analyzed. Remission rates and survival outcomes were evaluated. For analyses in context of ELN2022 classification, patients carrying an MR mutation were excluded from the adverse group and analyzed separately; those with co-occurring favorable or intermediate features remained in their respective groups. Overall, 1698 patients (34.1%) harbored at least one MR mutation. Lower complete remission rates were observed in MR-mutated cases (65.7% vs 77.7%; p < 0.001) along with shorter event-free (HR 1.45; p < 0.001), relapse-free (HR 1.33; p < 0.001), and overall survival (HR 1.45; p < 0.001) were recorded. Gene-specific prognostic patterns emerged: ASXL1, RUNX1, SF3B1, and U2AF1 mutations associated with adverse risk-like outcomes; SRSF2 and STAG2 aligned with intermediate-risk; BCOR, EZH2, and ZRSR2 did not differ significantly from intermediate or adverse risk. These findings from a large cooperative cohort highlight prognostic heterogeneity among MR mutations and suggest that SRSF2 and STAG2 mutations are associated with less adverse risk patterns, comparable to intermediate-risk.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"63-71"},"PeriodicalIF":13.4,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02781-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374020","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}
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