Pub Date : 2025-12-08DOI: 10.1038/s41375-025-02804-2
Theis Mikkelsen, Marianne Helenius, Mirella Ampatzidou, Andishe Attarbaschi, Liv Andres-Jensen, Arndt Borkhardt, Nuria Conde Cuevas, Gabriele Escherich, Melanie M. Hagleitner, Christina Halsey, Jonathan Josephs-Spaulding, Louise Lundgren, Simone Pehn, Sophia Polychronopoulou, Ulrik Stoltze, Linea Natalie Toksvang, Ayo Wahlberg, Stefanie Verena Junk, Kjeld Schmiegelow
Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.
{"title":"Role of common host genome variants in Childhood Acute Lymphoblastic Leukemia","authors":"Theis Mikkelsen, Marianne Helenius, Mirella Ampatzidou, Andishe Attarbaschi, Liv Andres-Jensen, Arndt Borkhardt, Nuria Conde Cuevas, Gabriele Escherich, Melanie M. Hagleitner, Christina Halsey, Jonathan Josephs-Spaulding, Louise Lundgren, Simone Pehn, Sophia Polychronopoulou, Ulrik Stoltze, Linea Natalie Toksvang, Ayo Wahlberg, Stefanie Verena Junk, Kjeld Schmiegelow","doi":"10.1038/s41375-025-02804-2","DOIUrl":"10.1038/s41375-025-02804-2","url":null,"abstract":"Childhood acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease, and while somatic alterations inform diagnosis and treatment stratification, germline variants - particularly common host genome variants - rarely influence clinical care. Over the past decade, various host genome variant studies have uncovered numerous common variants associated with ALL susceptibility, treatment efficacy, and toxicity risk. Yet, less than a handful have reached clinical implementation, with TPMT and NUDT15 variants being the only ones widely used clinically. Whether a variant can be readily translated into the clinical setting primarily depends on four features: (1) Phenotype severity, (2) phenotype rarity and the proportion of cases (overall or in subsets of patients) accounted for by genetic variants, (3) the application of the variant as an add-on clinical decision support tool, and (4) the availability, cost, and potential side effects of interventions and/or prophylaxis. Key barriers for such clinical translation include insufficient effect sizes, lack of replication across diverse populations, and lack of well-established treatment modification strategies. However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"3-24"},"PeriodicalIF":13.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02804-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704303","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 : 2025-12-08DOI: 10.1038/s41375-025-02840-y
Andreas Hochhaus, Robert Peter Gale
{"title":"40 years of LEUKEMIA","authors":"Andreas Hochhaus, Robert Peter Gale","doi":"10.1038/s41375-025-02840-y","DOIUrl":"10.1038/s41375-025-02840-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"1-2"},"PeriodicalIF":13.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02840-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708477","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 : 2025-12-03DOI: 10.1038/s41375-025-02814-0
Carmelo Gurnari, Hideki Makishima, Arda Durmaz, Enrico Attardi, Ryunosuke Saiki, Alex Bataller, Guilherme Sapinho, Lukasz Gondek, Yasuhito Nannya, Steve Best, Pramila Krishnamurthy, Kar Lok Kong, Yoshiko Atsuta, Senji Kasahara, Kazuma Ohyashiki, Yasushi Miyazaki, Nobuhiro Kanemura, Nobuhiro Hiramoto, Francesco Versino, Maria Julia Montoro, Sara Torres-Esquius, Andres Jerez Cayuela, Miguel López-Esteban, Carolina Martínez-Laperche, Hussein Awada, Valeria Visconte, Courtney D. DiNardo, Maria Teresa Voso, Amy E. DeZern, Guillermo Garcia-Manero, Austin G. Kulasekararaj, Jaroslaw P. Maciejewski, Seishi Ogawa
DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.
{"title":"DDX41-mutant myeloid neoplasms defy current prognostic schemes and require a dedicated risk scoring system: a multicenter, retrospective study","authors":"Carmelo Gurnari, Hideki Makishima, Arda Durmaz, Enrico Attardi, Ryunosuke Saiki, Alex Bataller, Guilherme Sapinho, Lukasz Gondek, Yasuhito Nannya, Steve Best, Pramila Krishnamurthy, Kar Lok Kong, Yoshiko Atsuta, Senji Kasahara, Kazuma Ohyashiki, Yasushi Miyazaki, Nobuhiro Kanemura, Nobuhiro Hiramoto, Francesco Versino, Maria Julia Montoro, Sara Torres-Esquius, Andres Jerez Cayuela, Miguel López-Esteban, Carolina Martínez-Laperche, Hussein Awada, Valeria Visconte, Courtney D. DiNardo, Maria Teresa Voso, Amy E. DeZern, Guillermo Garcia-Manero, Austin G. Kulasekararaj, Jaroslaw P. Maciejewski, Seishi Ogawa","doi":"10.1038/s41375-025-02814-0","DOIUrl":"10.1038/s41375-025-02814-0","url":null,"abstract":"DDX41-mutant myeloid neoplasia (MN) is characterized by unique clinical-molecular characteristics and prognosis. However, it is poorly understood how DDX41 mutational constellations drive MN outcomes. We leveraged collaborative resources to test the new 2022 MN diagnostic and prognostic schemes and account for the diverse mutational configurations of DDX41-mutant MN. Diagnostic re-classification from 2016 to 2022 schemes showed an overall shift of 14.9% and 29.7% for DDX41-mutant MDS and AML, respectively. Current prognostic systems (IPSS-R/M and ELN 2017/22) showed poor applicability to DDX41-mutant MN when compared to wild-type counterparts. Dissecting all possible DDX41 configurations, we assigned the greatest prognostic impact to R525H somatic and germline truncating hits. The former impacted most survival outcomes, while the latter were enriched in AML, independently predicting leukemic evolution. Such features had synergistic effects, albeit with different treatment interactions, and were included in DDX41-specific multivariable outcome models, which alleviated the shortcomings of the current prognostic MN algorithms. We here show that current prognostic tools are not able to adequately assess leukemic evolution and survival outcomes in DDX41-mutant MN. Additional risk factors inherent to this MN subentity hold a prognostic significance beyond the consideration of traditional disease-specific variables, substantiating the need for a dedicated risk scoring system.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"178-187"},"PeriodicalIF":13.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664236","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 : 2025-12-02DOI: 10.1038/s41375-025-02824-y
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/s41375-025-02824-y","DOIUrl":"10.1038/s41375-025-02824-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"261-261"},"PeriodicalIF":13.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02824-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661526","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 : 2025-11-20DOI: 10.1038/s41375-025-02808-y
David Vallois, Edoardo Missiaglia, Luis Veloza, Anja Fischer, Doriane Cavalieri, Vimel Rattina, Bettina Bisig, Vincent Roh, Laura Wiehle, Rita Sarkis, Emmanuel Bachy, Christophe Bonnet, Julie Bruneau, Anne Cairoli, Roland De Wind, Fanny Drieux, Romain Dubois, Jean-François Emile, Virginie Fataccioli, Kamel Laribi, Albane Ledoux-Pilon, François Lemonnier, Francisco Llamas-Gutierrez, Pierre Morel, Marie Parrens, Elsa Poullot, Leticia Quintanilla-Martinez, Jeremy Sandrini, Joan Somja, Luc Xerri, Olivier Tournilhac, Philippe Gaulard, Reiner Siebert, Laurence de Leval
Pub Date : 2025-11-18DOI: 10.1038/s41375-025-02796-z
Fausto Castagnetti, Massimo Breccia, Elisabetta Abruzzese, Renato Bassan, Gianni Binotto, Massimiliano Bonifacio, Giovanni Caocci, Isabella Capodanno, Francesco Cavazzini, Giuseppe Cimino, Paola Fazi, Antonella Gozzini, Alessandra Iurlo, Jeroen J. W. M. Janssen, Monia Lunghi, Roberto Marasca, Bruno Martino, Monica Messina, Francesco Muriano, Francesca Paoloni, Alfonso Piciocchi, Gianantonio Rosti, Antonella Russo Rossi, Giuseppe Saglio, Simona Sica, Simona Soverini, Agostino Tafuri, Daniele Vallisa, Peter E. Westerweel, Fabrizio Pane
Treatment-free remission is one of the most important goals of CML treatment but so far, the best treatment to reach this aim is still undefined, even though it is widely accepted that a sustained DMR is the prerequisite to discontinue TKI. Here we report on the depth of the molecular response, the first co-primary end point of the SUSTRENIM study, in a cohort of newly diagnosed CP-CML patients randomized 1:1 to be treated with nilotinib or with imatinib followed by switching to nilotinib in absence of optimal response. Of the 448 enrolled patients, 228 and 220 were randomized to the nilotinib (NIL) and imatinib (IM) arms, respectively, and followed for a median of 45.9 months. Eighty-two (37.2%) of the 220 patients on the IMarm did not fulfill the ELN criteria for optimal response of treatment and switched to nilotinib therapy. At the 24 months of follow-up, 107 of the 448 patients reached an MR4.5 response with a significantly higher frequency within the patients on the nilotinib arm (65 vs 42; p = 0.02). The analysis of the first primary endpoint indicates that, despite the early switch in the IM-randomized patients, NIL therapy is more effective to induce DMR.
无治疗缓解是CML治疗最重要的目标之一，但到目前为止，达到这一目标的最佳治疗方法仍然不明确，尽管人们普遍认为持续的DMR是停止TKI的先决条件。在这里，我们报告了分子反应的深度，SUSTRENIM研究的第一个共同主要终点，在一组新诊断的CP-CML患者中，随机1:1地接受尼罗替尼或伊马替尼治疗，然后在没有最佳反应的情况下切换到尼罗替尼。在448名入组患者中，228名和220名分别随机分配到尼罗替尼（NIL）和伊马替尼（IM）组，随访时间中位数为45.9个月。在接受IMarm治疗的220名患者中，有82名（37.2%）未达到ELN治疗最佳反应标准，转而使用尼罗替尼治疗。在24个月的随访中，448例患者中有107例达到MR4.5缓解，尼罗替尼组患者的MR4.5缓解频率显著高于尼罗替尼组（65 vs 42; p = 0.02）。对第一个主要终点的分析表明，尽管在im随机患者中早期切换，但NIL治疗更有效地诱导DMR。
{"title":"Nilotinib versus imatinib with early switch from imatinib to nilotinib to obtain treatment-free remission in newly diagnosed chronic myeloid leukemia patients: the analysis of the first co-primary endpoint","authors":"Fausto Castagnetti, Massimo Breccia, Elisabetta Abruzzese, Renato Bassan, Gianni Binotto, Massimiliano Bonifacio, Giovanni Caocci, Isabella Capodanno, Francesco Cavazzini, Giuseppe Cimino, Paola Fazi, Antonella Gozzini, Alessandra Iurlo, Jeroen J. W. M. Janssen, Monia Lunghi, Roberto Marasca, Bruno Martino, Monica Messina, Francesco Muriano, Francesca Paoloni, Alfonso Piciocchi, Gianantonio Rosti, Antonella Russo Rossi, Giuseppe Saglio, Simona Sica, Simona Soverini, Agostino Tafuri, Daniele Vallisa, Peter E. Westerweel, Fabrizio Pane","doi":"10.1038/s41375-025-02796-z","DOIUrl":"10.1038/s41375-025-02796-z","url":null,"abstract":"Treatment-free remission is one of the most important goals of CML treatment but so far, the best treatment to reach this aim is still undefined, even though it is widely accepted that a sustained DMR is the prerequisite to discontinue TKI. Here we report on the depth of the molecular response, the first co-primary end point of the SUSTRENIM study, in a cohort of newly diagnosed CP-CML patients randomized 1:1 to be treated with nilotinib or with imatinib followed by switching to nilotinib in absence of optimal response. Of the 448 enrolled patients, 228 and 220 were randomized to the nilotinib (NIL) and imatinib (IM) arms, respectively, and followed for a median of 45.9 months. Eighty-two (37.2%) of the 220 patients on the IMarm did not fulfill the ELN criteria for optimal response of treatment and switched to nilotinib therapy. At the 24 months of follow-up, 107 of the 448 patients reached an MR4.5 response with a significantly higher frequency within the patients on the nilotinib arm (65 vs 42; p = 0.02). The analysis of the first primary endpoint indicates that, despite the early switch in the IM-randomized patients, NIL therapy is more effective to induce DMR.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"47-54"},"PeriodicalIF":13.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02796-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536609","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 : 2025-11-18DOI: 10.1038/s41375-025-02801-5
Matthew Salmon, Nicole Naumann, Jenny Rinke, Manja Meggendorfer, Deepti Radia, Mark Pomfret, Thomas Ernst, Andreas Hochhaus, Andreas Reiter, William J. Tapper, Helen White, Nicholas C. P. Cross
Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints.
{"title":"Long read nanopore DNA sequencing with adaptive sampling to identify tyrosine kinase fusion genes","authors":"Matthew Salmon, Nicole Naumann, Jenny Rinke, Manja Meggendorfer, Deepti Radia, Mark Pomfret, Thomas Ernst, Andreas Hochhaus, Andreas Reiter, William J. Tapper, Helen White, Nicholas C. P. Cross","doi":"10.1038/s41375-025-02801-5","DOIUrl":"10.1038/s41375-025-02801-5","url":null,"abstract":"Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 1","pages":"37-46"},"PeriodicalIF":13.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02801-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145536090","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：