Pub Date : 2026-02-17DOI: 10.1038/s41375-026-02887-5
Thomas C. Wiemers, Nora Grieb, Maximilian Ferle, Michael Rade, David Fandrei, Patrick Born, Luise Fischer, Song-Yau Wang, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Ronny Baber, Markus Kreuz, Klaus H. Metzeler, Marco Herling, Carmen D. Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Andreas Boldt, Thomas Neumuth, Ulrike Köhl, Kristin Reiche, Tina Stegmann, Timm Denecke, Uwe Platzbecker, Vladan Vučinić, Hans-Jonas Meyer, Daniel Lavall, Maximilian Merz
{"title":"MyCARdiac score: integrating cardiac imaging and biomarkers to predict outcomes in RRMM patients receiving cilta-cel","authors":"Thomas C. Wiemers, Nora Grieb, Maximilian Ferle, Michael Rade, David Fandrei, Patrick Born, Luise Fischer, Song-Yau Wang, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Ronny Baber, Markus Kreuz, Klaus H. Metzeler, Marco Herling, Carmen D. Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Andreas Boldt, Thomas Neumuth, Ulrike Köhl, Kristin Reiche, Tina Stegmann, Timm Denecke, Uwe Platzbecker, Vladan Vučinić, Hans-Jonas Meyer, Daniel Lavall, Maximilian Merz","doi":"10.1038/s41375-026-02887-5","DOIUrl":"https://doi.org/10.1038/s41375-026-02887-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"20 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205010","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 : 2026-02-17DOI: 10.1038/s41375-026-02883-9
Samarpana Chakraborty, Claudia Morganti, Kimberly Zaldana, Bianca Rivera Pena, Hui Zhang, Divij Verma, Nadege Gitego, Feiyang Ma, Srinivas Aluri, Kith Pradhan, Shanisha Gordon-Mitchell, Ioannis Mantzaris, Mendel Goldfinger, Eric Feldman, Kira Gritsman, Yang Shi, Stefan Hubner, Yi Hua Qiu, Brandon D. Brown, Abdullah Khasawneh, Anna Skwarska, Eduardo Sabino de Camargo Magalhães, Amit Verma, Marina Konopleva, Yoko Tabe, Evripidis Gavathiotis, Simona Colla, Jared Gollob, Joyoti Dey, Steven M. Kornblau, Sergei B. Koralov, Keisuke Ito, Aditi Shastri
Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader.
{"title":"A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid leukemia","authors":"Samarpana Chakraborty, Claudia Morganti, Kimberly Zaldana, Bianca Rivera Pena, Hui Zhang, Divij Verma, Nadege Gitego, Feiyang Ma, Srinivas Aluri, Kith Pradhan, Shanisha Gordon-Mitchell, Ioannis Mantzaris, Mendel Goldfinger, Eric Feldman, Kira Gritsman, Yang Shi, Stefan Hubner, Yi Hua Qiu, Brandon D. Brown, Abdullah Khasawneh, Anna Skwarska, Eduardo Sabino de Camargo Magalhães, Amit Verma, Marina Konopleva, Yoko Tabe, Evripidis Gavathiotis, Simona Colla, Jared Gollob, Joyoti Dey, Steven M. Kornblau, Sergei B. Koralov, Keisuke Ito, Aditi Shastri","doi":"10.1038/s41375-026-02883-9","DOIUrl":"https://doi.org/10.1038/s41375-026-02883-9","url":null,"abstract":"Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"326 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205009","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 : 2026-02-17DOI: 10.1038/s41375-026-02865-x
Nicholas C. Lee, Rui Miao, Neal S. Young
{"title":"Reframing—renaming(?)—myelodysplastic syndromes/neoplasms and clonal hematopoiesis of indeterminate potential","authors":"Nicholas C. Lee, Rui Miao, Neal S. Young","doi":"10.1038/s41375-026-02865-x","DOIUrl":"https://doi.org/10.1038/s41375-026-02865-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"126 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205302","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 : 2026-02-17DOI: 10.1038/s41375-026-02870-0
Daniel J. Landsburg, Nancy Musoke, Caren Gentile, Taylor R. Brooks, Sunita D. Nasta, Stefan K. Barta, Jordan S. Carter, Elise A. Chong, Jakub Svoboda, Stephen J. Schuster, Colin J. Thomas, Emily B. Tomasulo, Michael R. Cook, Jennifer J. D. Morrissette, Paolo F. Caimi, Brian T. Hill
{"title":"Prognostic impact of TP53 alterations in cases of newly diagnosed large B-cell lymphoma","authors":"Daniel J. Landsburg, Nancy Musoke, Caren Gentile, Taylor R. Brooks, Sunita D. Nasta, Stefan K. Barta, Jordan S. Carter, Elise A. Chong, Jakub Svoboda, Stephen J. Schuster, Colin J. Thomas, Emily B. Tomasulo, Michael R. Cook, Jennifer J. D. Morrissette, Paolo F. Caimi, Brian T. Hill","doi":"10.1038/s41375-026-02870-0","DOIUrl":"https://doi.org/10.1038/s41375-026-02870-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146205007","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 : 2026-02-12DOI: 10.1038/s41375-026-02884-8
Jing Gao, Xiaohong Zhao, Qing Yin, Allen Hu, Kevin Qiu, Loryn Blackburn, Lenny Lei, Rui Xiong, Chengfeng Bi, Jeffrey W Craig, Craig A Portell, Marco L Davila, Michael E Williams, Jianguo Tao
Aggressive B-cell lymphomas, driven by MYC overexpression, exhibit rapid progression, resistance to therapies, and poor survival. While chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable clinical efficacy in B-cell lymphomas, nearly half of patients who initially respond to CAR-T therapy eventually develop resistance and disease progression. In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845. MCL-1 inhibition downregulates MYC and activates the STAT1-interferon inflammatory pathway, promoting cytotoxic T-cell infiltration with reduced tumor-associated myeloid cells both in vitro and in vivo. Sublethal dose of the MCL-1i enhances TME immunogenicity and reawakens anti-tumor immune responses in murine models. We show that MCL-1i and CD19-targeted CAR-T cells reciprocally overcome resistance to each single-agent therapy, and combining MCL-1i with CD19 CAR-T cells significantly improves treatment efficacy, resulting in near-complete eradication of MYC-driven lymphoma in vivo. Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.
{"title":"Synthetic lethality of MCL-1 inhibition and CAR-T therapy in aggressive B-cell lymphoma.","authors":"Jing Gao, Xiaohong Zhao, Qing Yin, Allen Hu, Kevin Qiu, Loryn Blackburn, Lenny Lei, Rui Xiong, Chengfeng Bi, Jeffrey W Craig, Craig A Portell, Marco L Davila, Michael E Williams, Jianguo Tao","doi":"10.1038/s41375-026-02884-8","DOIUrl":"https://doi.org/10.1038/s41375-026-02884-8","url":null,"abstract":"<p><p>Aggressive B-cell lymphomas, driven by MYC overexpression, exhibit rapid progression, resistance to therapies, and poor survival. While chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable clinical efficacy in B-cell lymphomas, nearly half of patients who initially respond to CAR-T therapy eventually develop resistance and disease progression. In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845. MCL-1 inhibition downregulates MYC and activates the STAT1-interferon inflammatory pathway, promoting cytotoxic T-cell infiltration with reduced tumor-associated myeloid cells both in vitro and in vivo. Sublethal dose of the MCL-1i enhances TME immunogenicity and reawakens anti-tumor immune responses in murine models. We show that MCL-1i and CD19-targeted CAR-T cells reciprocally overcome resistance to each single-agent therapy, and combining MCL-1i with CD19 CAR-T cells significantly improves treatment efficacy, resulting in near-complete eradication of MYC-driven lymphoma in vivo. Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146180280","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 : 2026-02-11DOI: 10.1038/s41375-026-02863-z
Valeria Soberón, Lena Osswald, Andrew Moore, Dominika Sosnowska, Gene Swinerd, Jingyu Chen, Seren Baygün, Carina Diehl, Gönül Seyhan, Laura Kraus, Vanessa Gölling, Ricarda Trapp, Thomas J O'Neill, Sabrina Bortoluzzi, Daniel Kovacs, Tim Ammon, Pankaj Singroul, Yuliia Hubarzhevska, Rupert Öllinger, Sebastian Mueller, Olga Baranov, Piero Giansanti, Felix Gillhuber, Sonja Grath, Oliver Weigert, Andreas Rosenwald, Yoshiteru Sasaki, Klaus Rajewsky, Katja Steiger, Florian Bassermann, Roland Rad, Daniel Krappmann, Ingo Ringshausen, Marc Schmidt-Supprian
{"title":"Correction: Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies.","authors":"Valeria Soberón, Lena Osswald, Andrew Moore, Dominika Sosnowska, Gene Swinerd, Jingyu Chen, Seren Baygün, Carina Diehl, Gönül Seyhan, Laura Kraus, Vanessa Gölling, Ricarda Trapp, Thomas J O'Neill, Sabrina Bortoluzzi, Daniel Kovacs, Tim Ammon, Pankaj Singroul, Yuliia Hubarzhevska, Rupert Öllinger, Sebastian Mueller, Olga Baranov, Piero Giansanti, Felix Gillhuber, Sonja Grath, Oliver Weigert, Andreas Rosenwald, Yoshiteru Sasaki, Klaus Rajewsky, Katja Steiger, Florian Bassermann, Roland Rad, Daniel Krappmann, Ingo Ringshausen, Marc Schmidt-Supprian","doi":"10.1038/s41375-026-02863-z","DOIUrl":"10.1038/s41375-026-02863-z","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165721","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 : 2026-02-10DOI: 10.1038/s41375-026-02873-x
Camilla Grud Nielsen, Bodil Als-Nielsen, Birgitte Klug Albertsen, Ólafur Birgir Davídsson, Andreja Dimitrijevic, Henrik Hjalgrim, Marianne Ifversen, Louise Lundgren, Line Stensig Lynggaard, Marianne Olsen, Ulrik Malthe Overgaard, Cecilie Utke Rank, Mathias Rathe, Klaus Rostgaard, Kjeld Schmiegelow, Liv Andrés-Jensen
With increasing survival in acute lymphoblastic leukemia (ALL), long-term toxicities have become a critical aspect. A novel measure, designated Severe Toxicity-free survival (STFS), was developed through international consensus to integrate the most severe, symptomatic organ toxicities in outcome evaluation. This measure has not been applied to real-world data before. We assessed the incidence of 21 predefined Severe Toxicities in a nationwide cohort of 506 ALL patients aged 1–45 years treated according to the NOPHO ALL2008 protocol. At five years, event-free survival was 84.4% (95% CI: 81.3–87.7%) and Severe Toxicity-event-free survival was 78.4% (95% CI: 74.9–82.1%), with significantly lower values in adults (aged 18–45 years) than children (61.6% [52.6–72.2%] vs 82.4% [78.8–86.2%]; log-rank p < 0.001). The most common Severe Toxicities were severe osteonecrosis limiting activities of daily function (N = 20) and disabling paralytic and neuropathic conditions (N = 16). Exploratory analyses showed that 10–17-year-olds had the highest risk of Severe Toxicities similar to that of adults. These findings highlight a burden of severe, long-term toxicities in ALL survivors overlooked by traditional outcome measures, also following frontline therapy only. STFS should be incorporated in future trials for meaningful outcome evaluation and international comparisons across treatment strategies.
{"title":"Severe toxicity-free survival following acute lymphoblastic leukemia in patients aged 1–45 years: a Danish cohort study","authors":"Camilla Grud Nielsen, Bodil Als-Nielsen, Birgitte Klug Albertsen, Ólafur Birgir Davídsson, Andreja Dimitrijevic, Henrik Hjalgrim, Marianne Ifversen, Louise Lundgren, Line Stensig Lynggaard, Marianne Olsen, Ulrik Malthe Overgaard, Cecilie Utke Rank, Mathias Rathe, Klaus Rostgaard, Kjeld Schmiegelow, Liv Andrés-Jensen","doi":"10.1038/s41375-026-02873-x","DOIUrl":"https://doi.org/10.1038/s41375-026-02873-x","url":null,"abstract":"With increasing survival in acute lymphoblastic leukemia (ALL), long-term toxicities have become a critical aspect. A novel measure, designated Severe Toxicity-free survival (STFS), was developed through international consensus to integrate the most severe, symptomatic organ toxicities in outcome evaluation. This measure has not been applied to real-world data before. We assessed the incidence of 21 predefined Severe Toxicities in a nationwide cohort of 506 ALL patients aged 1–45 years treated according to the NOPHO ALL2008 protocol. At five years, event-free survival was 84.4% (95% CI: 81.3–87.7%) and Severe Toxicity-event-free survival was 78.4% (95% CI: 74.9–82.1%), with significantly lower values in adults (aged 18–45 years) than children (61.6% [52.6–72.2%] vs 82.4% [78.8–86.2%]; log-rank p < 0.001). The most common Severe Toxicities were severe osteonecrosis limiting activities of daily function (N = 20) and disabling paralytic and neuropathic conditions (N = 16). Exploratory analyses showed that 10–17-year-olds had the highest risk of Severe Toxicities similar to that of adults. These findings highlight a burden of severe, long-term toxicities in ALL survivors overlooked by traditional outcome measures, also following frontline therapy only. STFS should be incorporated in future trials for meaningful outcome evaluation and international comparisons across treatment strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"92 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146152276","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 : 2026-02-09DOI: 10.1038/s41375-026-02874-w
Rabea Mecklenbrauck, Angela Villaverde Ramiro, Eric Sträng, Razif Gabdoulline, Javier Martinez Elicegui, Marta Sobas, Lisa Pleyer, Amin Turki, Maria Teresa Voso, Axel Benner, Alberto Hernández-Sánchez, Jesse M Tettero, Laura Tur Gimenez, Klaus H Metzeler, Guadalupe Oñate, Sören Lehmann, Brian Jp Huntly, Ian Thomas, Felicitas R Thol, Florian H Heidel, Peter Jm Valk, Konstanze Döhner, Torsten Haferlach, Kenneth I Mills, Hartmut Döhner, Gastone Castellani, Gert J Ossenkoppele, Jesus María Hernández-Rivas, Lars Bullinger, Michael Heuser
The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.
将9种骨髓增生异常相关基因（MRG）突变（ASXL1、bor、EZH2、RUNX1、SF3B1、SRSF2、STAG2、U2AF1、ZRSR2）作为不良危险因素纳入ELN风险分类，重塑了急性髓性白血病（AML）的分类。AML伴有FLT3-ITD突变和同时发生的MRG改变现在被归类为ELN不良风险组，尽管支持证据仍然有限。在HARMONY平台中包含可用分子信息的4078例AML患者中，862例携带FLT3-ITD突变并接受了强化化疗。其中，171例（20%）在诊断时表现出共同发生的MRG突变。在这个队列中，mrg与无复发生存期（RFS）或总生存期（OS）没有独立的相关性。在FLT3-ITD/NPM1共突变亚组中，MRG突变很少见（9%），对预后没有影响。相反，在FLT3-ITD/NPM1野生型AML中，在多变量分析中，MRG突变可预测较短的RFS （HR 1.37, 95%CI 1.01 - 1.88, p = 0.046）和OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032)，其生存时间与ELN不良风险类别相当。FLT3-ITD的等位基因比例并不能进一步划分该亚组的OS和RFS。这些发现表明，FLT3-ITD AML中MRG突变的预后相关性是由NPM1共突变状态和缺乏FLT3-ITD AML中的镜像结果调节的。
{"title":"Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia.","authors":"Rabea Mecklenbrauck, Angela Villaverde Ramiro, Eric Sträng, Razif Gabdoulline, Javier Martinez Elicegui, Marta Sobas, Lisa Pleyer, Amin Turki, Maria Teresa Voso, Axel Benner, Alberto Hernández-Sánchez, Jesse M Tettero, Laura Tur Gimenez, Klaus H Metzeler, Guadalupe Oñate, Sören Lehmann, Brian Jp Huntly, Ian Thomas, Felicitas R Thol, Florian H Heidel, Peter Jm Valk, Konstanze Döhner, Torsten Haferlach, Kenneth I Mills, Hartmut Döhner, Gastone Castellani, Gert J Ossenkoppele, Jesus María Hernández-Rivas, Lars Bullinger, Michael Heuser","doi":"10.1038/s41375-026-02874-w","DOIUrl":"https://doi.org/10.1038/s41375-026-02874-w","url":null,"abstract":"<p><p>The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150036","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 : 2026-02-09DOI: 10.1038/s41375-026-02878-6
Rohtesh S Mehta, Shannon R McCurdy, Filippo Milano, Mariam Nawas, Yosra Aljawai, Joseph Cataquiz Rimando, Taha Al-Juhaishi, Annie Im, Jennifer A Kanakry, Aleksandr Lazaryan, Christopher G Kanakry
{"title":"Challenging a clinical dogma with multimodal machine learning: a retrospective analysis of transplant mismatched donor selection.","authors":"Rohtesh S Mehta, Shannon R McCurdy, Filippo Milano, Mariam Nawas, Yosra Aljawai, Joseph Cataquiz Rimando, Taha Al-Juhaishi, Annie Im, Jennifer A Kanakry, Aleksandr Lazaryan, Christopher G Kanakry","doi":"10.1038/s41375-026-02878-6","DOIUrl":"https://doi.org/10.1038/s41375-026-02878-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150082","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 : 2026-02-04DOI: 10.1038/s41375-026-02861-1
Anna Nikkarinen, Jonas Almlöf, Albin Österroos, Claes Ladenvall, Rose-Marie Amini, Peter Hollander, Kristin Ayoola Gustafsson, Panagiotis Baliakas, Ingrid Glimelius
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