Pub Date : 2026-01-07DOI: 10.1038/s41375-025-02841-x
Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa
B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.
{"title":"Alnuctamab, a bivalent B-cell maturation antigen-targeting T cell engager for patients with relapsed or refractory multiple myeloma: results from a phase 1, first-in-human study","authors":"Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa","doi":"10.1038/s41375-025-02841-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02841-x","url":null,"abstract":"B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908162","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}
Aggressive NK-cell leukemia (ANKL) is a rare NK-cell leukemia characterized by, an aggressive clinical course, and frequent Epstein–Barr virus association. We retrospectively collected 126 ANKL patients diagnosed between 2000 and 2021 from 71 institutes; 108 were evaluable for analysis to characterize the recent advances. The median age was 49 years (range: 17–90), and 63 patients were male. The median percentage of leukemic cells in the bone marrow and peripheral blood was 19.7% and 10.0%, respectively. The first-line regimens included SMILE (n = 38, 42%), CHOP(-like) (n = 26, 29%), DeVIC (n = 15, 17%), and other L-asparaginase-containing regimens (n = 8, 9%), with the overall response rates of 66%, 31%, 33%, and 50%, respectively. Median overall survival (OS) was 5.5 months, with a 2-year OS of 18.7%. Patients treated with SMILE had significantly better OS than others (2-year OS 30.1% vs. 7.0%; P < 0.001). Prognosis further improved with allogeneic hematopoietic stem cell transplantation (HSCT) (2-year OS 37.2% vs 3.5%; P < 0.001). Multivariate analysis confirmed treatment with SMILE [hazard ratio (HR) 0.53, 95% confidential interval (CI) 0.31–0.88] and allogeneic HSCT (HR 0.33, 95% CI 0.18–0.61) as independent favorable factors. In conclusion, SMILE chemotherapy followed by allogeneic HSCT may improve outcomes in ANKL.
侵袭性nk细胞白血病（ANKL）是一种罕见的nk细胞白血病，其特点是具有侵袭性的临床病程和频繁的爱泼斯坦-巴尔病毒关联。我们回顾性收集了2000年至2021年间从71个研究所诊断的126例ANKL患者；其中108项可用于分析，以描述最近的进展。中位年龄49岁（17-90岁），男性63例。骨髓和外周血中白血病细胞的中位数百分比分别为19.7%和10.0%。一线方案包括SMILE （n = 38, 42%）、CHOP(-like) （n = 26, 29%）、DeVIC （n = 15, 17%）和其他含l -天冬酰胺酶方案（n = 8, 9%），总有效率分别为66%、31%、33%和50%。中位总生存期（OS）为5.5个月，2年OS为18.7%。SMILE治疗患者的OS明显优于其他治疗组（2年OS 30.1% vs. 7.0%; P < 0.001）。同种异体造血干细胞移植（HSCT）的预后进一步改善（2年生存率37.2% vs 3.5%; P < 0.001）。多因素分析证实SMILE治疗[危险比（HR） 0.53, 95%可信区间（CI） 0.31-0.88]和异体造血干细胞移植（HR 0.33, 95% CI 0.18-0.61）是独立的有利因素。总之，SMILE化疗配合同种异体造血干细胞移植可能改善ANKL的预后。
{"title":"Advances in the treatment and prognosis of aggressive NK-cell leukemia: results from the ANKL22 study","authors":"Ayumi Fujimoto, Takeshi Maeda, Noriko Doki, Noriko Fukuhara, Noriko Iwaki, Nobuhiro Hiramoto, Hideki Goto, Takuya Miyazaki, Ikue Shiki, Kana Miyazaki, Motoko Yamaguchi, Fumihiro Ishida, Ritsuro Suzuki","doi":"10.1038/s41375-025-02854-6","DOIUrl":"10.1038/s41375-025-02854-6","url":null,"abstract":"Aggressive NK-cell leukemia (ANKL) is a rare NK-cell leukemia characterized by, an aggressive clinical course, and frequent Epstein–Barr virus association. We retrospectively collected 126 ANKL patients diagnosed between 2000 and 2021 from 71 institutes; 108 were evaluable for analysis to characterize the recent advances. The median age was 49 years (range: 17–90), and 63 patients were male. The median percentage of leukemic cells in the bone marrow and peripheral blood was 19.7% and 10.0%, respectively. The first-line regimens included SMILE (n = 38, 42%), CHOP(-like) (n = 26, 29%), DeVIC (n = 15, 17%), and other L-asparaginase-containing regimens (n = 8, 9%), with the overall response rates of 66%, 31%, 33%, and 50%, respectively. Median overall survival (OS) was 5.5 months, with a 2-year OS of 18.7%. Patients treated with SMILE had significantly better OS than others (2-year OS 30.1% vs. 7.0%; P < 0.001). Prognosis further improved with allogeneic hematopoietic stem cell transplantation (HSCT) (2-year OS 37.2% vs 3.5%; P < 0.001). Multivariate analysis confirmed treatment with SMILE [hazard ratio (HR) 0.53, 95% confidential interval (CI) 0.31–0.88] and allogeneic HSCT (HR 0.33, 95% CI 0.18–0.61) as independent favorable factors. In conclusion, SMILE chemotherapy followed by allogeneic HSCT may improve outcomes in ANKL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"373-382"},"PeriodicalIF":13.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908161","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 : 2025-12-23DOI: 10.1038/s41375-025-02832-y
Yueyao Yang, Xun Liu, Jing Wei, Jia Qin, Qinling Tan, Jie Ji, Fukun Guo, Yi Zheng, Feng Bi, Ming Liu, Gang Wang
Approximately 50% of B-ALL patients exhibit Blinatumomab (CD3/CD19 bispecific T-cell engager, BiTE) resistance, often with high tumor PD-L1 expression, limiting therapeutic efficacy. Combining Blinatumomab with PD-L1 blockade is promising but hindered by continuous infusion, short half-life, and high costs. We developed an economical, non-viral, single-dose intramuscular plasmid gene delivery for sustained (≥4 weeks) in vivo co-expression of CD3/CD19 BiTE and PD-L1 antibodies. This platform integrates T-cell-mediated cytotoxicity, immune checkpoint blockade, and antibody-dependent cytotoxicity. This strategy induced substantial leukemia cell regression, achieving an 80% complete remission (CR) rate in CD19⁺/PD-L1⁺ Nalm-6 xenografts and a 40% CR rate in the CD19 antigen-loss immune escape model. Anti-leukemic efficacy correlated with enhanced CD3⁺, CD8⁺ T-cell, CD3⁺CD56⁺ NKT-like cell expansion, and increased granzyme B/IFN-γ levels. Furthermore, in vivo-produced antibodies promoted B-ALL patient-derived CD3⁺ T-cell proliferation and CD19⁺ tumor cell clearance. This study presents a cost-effective, durable, and potent in vivo immunotherapy integrating T-cell engagement and PD-L1 blockade, offering a promising translational approach for B-ALL.
{"title":"In vivo expression of CD3/CD19 bispecific T-cell engager and α-PD-L1-Fc enables effective and durable immunotherapy for CD19+/PD-L1+ leukemia","authors":"Yueyao Yang, Xun Liu, Jing Wei, Jia Qin, Qinling Tan, Jie Ji, Fukun Guo, Yi Zheng, Feng Bi, Ming Liu, Gang Wang","doi":"10.1038/s41375-025-02832-y","DOIUrl":"10.1038/s41375-025-02832-y","url":null,"abstract":"Approximately 50% of B-ALL patients exhibit Blinatumomab (CD3/CD19 bispecific T-cell engager, BiTE) resistance, often with high tumor PD-L1 expression, limiting therapeutic efficacy. Combining Blinatumomab with PD-L1 blockade is promising but hindered by continuous infusion, short half-life, and high costs. We developed an economical, non-viral, single-dose intramuscular plasmid gene delivery for sustained (≥4 weeks) in vivo co-expression of CD3/CD19 BiTE and PD-L1 antibodies. This platform integrates T-cell-mediated cytotoxicity, immune checkpoint blockade, and antibody-dependent cytotoxicity. This strategy induced substantial leukemia cell regression, achieving an 80% complete remission (CR) rate in CD19⁺/PD-L1⁺ Nalm-6 xenografts and a 40% CR rate in the CD19 antigen-loss immune escape model. Anti-leukemic efficacy correlated with enhanced CD3⁺, CD8⁺ T-cell, CD3⁺CD56⁺ NKT-like cell expansion, and increased granzyme B/IFN-γ levels. Furthermore, in vivo-produced antibodies promoted B-ALL patient-derived CD3⁺ T-cell proliferation and CD19⁺ tumor cell clearance. This study presents a cost-effective, durable, and potent in vivo immunotherapy integrating T-cell engagement and PD-L1 blockade, offering a promising translational approach for B-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"348-359"},"PeriodicalIF":13.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808182","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 : 2025-12-23DOI: 10.1038/s41375-025-02836-8
Alexandre Guy, Olivier Mansier, Matisse Decilap, Alexandre Catherineau, Geoffrey Garcia, Sylvie Labrouche-Colomer, Marie-Lise Bats, Françoise Boyer, Jean-Christophe Ianotto, Eric Lippert, Lydia Roy, Suzanne Tavitian, Borhane Slama, Stéphane Girault, Gabriel Etienne, Anne Parry, Arnaud Saint-Lezer, Guillaume Denis, Clémence Médiavilla, Jean-François Viallard, Laurence Legros, Dana Ranta, Mathieu Wemeau, Franck-Emmanuel Nicolini, François Lifermann, Nathalie Cambier, Luc Darnige, François Girodon, Juliette Soret-Dulphy, Émilie Cayssials, Fabienne Vacheret, Léa Sureau, Damien Luque Paz, Valérie Ugo, Jean-Jacques Kiladjian, Rodolphe Thiébaut, Chloe James, on behalf of the French Intergroup of Myeloproliferative Neoplasms (FIM)
Thrombotic risk assessment is crucial in newly diagnosed essential thrombocythemia (ET) and polycythemia vera (PV) patients to guide cytoreductive therapy. We assessed whether thromboinflammation biomarkers would be good candidates to improve thrombosis risk stratification. We prospectively enrolled 394 newly diagnosed, cytoreductive therapy–naïve, ET and PV patients. We measured seven plasma biomarkers of neutrophil, monocyte, platelet, and endothelial activation, including NET markers, and evaluated their association with thrombosis risk scores at diagnosis. Multivariable analysis in the whole MPN cohort showed elevated calprotectin and tissue factor levels in high-risk versus low-risk patients using the conventional two-tiered score. This was also observed in ET patients only, but not in PV patients. Patients with a JAK2V617F allele burden >20% showed higher levels of three markers, including calprotectin, supporting its role in immunothrombosis. In PV patients, calprotectin correlated with the Venous Thrombosis Score (VETS), and five markers were elevated in those with prior venous thrombosis. Lastly, aspirin use was associated with lower H3Cit levels in patients with normal platelet counts, confirming its beneficial effect on NET formation. This is the largest study to date linking thromboinflammation markers to thrombotic risk in MPN patients and identifying potential biomarkers for future thrombosis risk scores.
{"title":"Thromboinflammation is associated with high thrombotic risk in patients with newly diagnosed myeloproliferative neoplasms","authors":"Alexandre Guy, Olivier Mansier, Matisse Decilap, Alexandre Catherineau, Geoffrey Garcia, Sylvie Labrouche-Colomer, Marie-Lise Bats, Françoise Boyer, Jean-Christophe Ianotto, Eric Lippert, Lydia Roy, Suzanne Tavitian, Borhane Slama, Stéphane Girault, Gabriel Etienne, Anne Parry, Arnaud Saint-Lezer, Guillaume Denis, Clémence Médiavilla, Jean-François Viallard, Laurence Legros, Dana Ranta, Mathieu Wemeau, Franck-Emmanuel Nicolini, François Lifermann, Nathalie Cambier, Luc Darnige, François Girodon, Juliette Soret-Dulphy, Émilie Cayssials, Fabienne Vacheret, Léa Sureau, Damien Luque Paz, Valérie Ugo, Jean-Jacques Kiladjian, Rodolphe Thiébaut, Chloe James, on behalf of the French Intergroup of Myeloproliferative Neoplasms (FIM)","doi":"10.1038/s41375-025-02836-8","DOIUrl":"10.1038/s41375-025-02836-8","url":null,"abstract":"Thrombotic risk assessment is crucial in newly diagnosed essential thrombocythemia (ET) and polycythemia vera (PV) patients to guide cytoreductive therapy. We assessed whether thromboinflammation biomarkers would be good candidates to improve thrombosis risk stratification. We prospectively enrolled 394 newly diagnosed, cytoreductive therapy–naïve, ET and PV patients. We measured seven plasma biomarkers of neutrophil, monocyte, platelet, and endothelial activation, including NET markers, and evaluated their association with thrombosis risk scores at diagnosis. Multivariable analysis in the whole MPN cohort showed elevated calprotectin and tissue factor levels in high-risk versus low-risk patients using the conventional two-tiered score. This was also observed in ET patients only, but not in PV patients. Patients with a JAK2V617F allele burden >20% showed higher levels of three markers, including calprotectin, supporting its role in immunothrombosis. In PV patients, calprotectin correlated with the Venous Thrombosis Score (VETS), and five markers were elevated in those with prior venous thrombosis. Lastly, aspirin use was associated with lower H3Cit levels in patients with normal platelet counts, confirming its beneficial effect on NET formation. This is the largest study to date linking thromboinflammation markers to thrombotic risk in MPN patients and identifying potential biomarkers for future thrombosis risk scores.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"360-372"},"PeriodicalIF":13.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808184","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 : 2025-12-22DOI: 10.1038/s41375-025-02829-7
Thanh Thanh T. Dinh, Matthew R. Lordo, Amy Y. Zhang, Chinmayee Goda, Nikolas Shilo, Ekaterina Altynova, Michael Ruesch, Parker Kronen, Megan Broughton, Erin Jeremy, Victoria L. Sellers, Xiaoli Zhang, Karilyn T. Larkin, Patrick L. Collins, Adrienne M. Dorrance, Aharon G. Freud, Christopher C. Oakes, Bethany L. Mundy- Bosse
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is incompletely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity through cytokine secretion. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. The transcription factor, aryl hydrocarbon receptor (AHR) is required for ILC3 development and function, and AML blasts have been shown to secrete AHR ligands. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation in ILC precursors. ILC3s developed in leukemic settings had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by ILC3-derived TNFα and GM-CSF. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo and human ILC3 frequency was associated with adverse risk stratification in AML patients. These data support a model in which AML promotes ILC3 expansion and function via an AHR-dependent mechanism to aid AML growth and survival.
{"title":"Leukemia-driven expansion of type 3 innate lymphoid cell facilitates a pro-tumoral microenvironment in acute myeloid leukemia","authors":"Thanh Thanh T. Dinh, Matthew R. Lordo, Amy Y. Zhang, Chinmayee Goda, Nikolas Shilo, Ekaterina Altynova, Michael Ruesch, Parker Kronen, Megan Broughton, Erin Jeremy, Victoria L. Sellers, Xiaoli Zhang, Karilyn T. Larkin, Patrick L. Collins, Adrienne M. Dorrance, Aharon G. Freud, Christopher C. Oakes, Bethany L. Mundy- Bosse","doi":"10.1038/s41375-025-02829-7","DOIUrl":"10.1038/s41375-025-02829-7","url":null,"abstract":"Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is incompletely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity through cytokine secretion. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. The transcription factor, aryl hydrocarbon receptor (AHR) is required for ILC3 development and function, and AML blasts have been shown to secrete AHR ligands. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation in ILC precursors. ILC3s developed in leukemic settings had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by ILC3-derived TNFα and GM-CSF. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo and human ILC3 frequency was associated with adverse risk stratification in AML patients. These data support a model in which AML promotes ILC3 expansion and function via an AHR-dependent mechanism to aid AML growth and survival.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"325-338"},"PeriodicalIF":13.4,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02829-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801567","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 : 2025-12-22DOI: 10.1038/s41375-025-02834-w
Martin Grözinger, Muriel Schlanke, Jana Gröne, Stella Erdmann, Marina Hajiyianni, Alexandra M. Poos, Heidi Thierjung, Elias K. Mai, Sandra Sauer, Dorothee Kaudewitz, Kaya Veelken, Christian S. Michel, Jan Hendrik Frenking, Lilli Sophie Sester, Tim Frederik Weber, Sam Sedaghat, Markus Wennmann, Carsten Müller-Tidow, Heinz-Peter Schlemmer, Stefan Delorme, Marc S. Raab, Hartmut Goldschmidt, Niels Weinhold, Lukas John
Whole-body imaging plays a critical role in assessing multiple myeloma (MM). The structured scoring systems MY-RADS and KIM score have primarily been developed for newly diagnosed patients (NDMM). However, their application and prognostic significance in relapsed/refractory multiple myeloma (RRMM) remains uncertain. To clarify this, we evaluated whole body magnetic resonance imaging (MRI) data from 46 RRMM patients and compared findings to 68 NDMM patients from the GMMG-HD7 trial using both scoring systems. Despite similar overall disease burden, RRMM patients showed significant differences, characterized by increased paramedullary and extramedullary disease and reduced diffuse marrow infiltration compared to NDMM. Both MY-RADS and KIM scores independently correlated with progression-free and overall survival in RRMM. These results highlight distinct biological patterns in RRMM, emphasizing a shift towards bone marrow-independent growth. Our findings suggest that in RRMM, iliac crest biopsies may underestimate disease burden, underlining the importance of imaging complementing bone marrow diagnostics.
{"title":"Structured whole-body MRI highlights clinically relevant disease pattern changes in relapsed/refractory multiple myeloma","authors":"Martin Grözinger, Muriel Schlanke, Jana Gröne, Stella Erdmann, Marina Hajiyianni, Alexandra M. Poos, Heidi Thierjung, Elias K. Mai, Sandra Sauer, Dorothee Kaudewitz, Kaya Veelken, Christian S. Michel, Jan Hendrik Frenking, Lilli Sophie Sester, Tim Frederik Weber, Sam Sedaghat, Markus Wennmann, Carsten Müller-Tidow, Heinz-Peter Schlemmer, Stefan Delorme, Marc S. Raab, Hartmut Goldschmidt, Niels Weinhold, Lukas John","doi":"10.1038/s41375-025-02834-w","DOIUrl":"10.1038/s41375-025-02834-w","url":null,"abstract":"Whole-body imaging plays a critical role in assessing multiple myeloma (MM). The structured scoring systems MY-RADS and KIM score have primarily been developed for newly diagnosed patients (NDMM). However, their application and prognostic significance in relapsed/refractory multiple myeloma (RRMM) remains uncertain. To clarify this, we evaluated whole body magnetic resonance imaging (MRI) data from 46 RRMM patients and compared findings to 68 NDMM patients from the GMMG-HD7 trial using both scoring systems. Despite similar overall disease burden, RRMM patients showed significant differences, characterized by increased paramedullary and extramedullary disease and reduced diffuse marrow infiltration compared to NDMM. Both MY-RADS and KIM scores independently correlated with progression-free and overall survival in RRMM. These results highlight distinct biological patterns in RRMM, emphasizing a shift towards bone marrow-independent growth. Our findings suggest that in RRMM, iliac crest biopsies may underestimate disease burden, underlining the importance of imaging complementing bone marrow diagnostics.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"339-347"},"PeriodicalIF":13.4,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02834-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801604","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 : 2025-12-19DOI: 10.1038/s41375-025-02842-w
Christine E. Birdwell, Warren Fiskus, Christopher P. Mill, Tapan M. Kadia, Naval Daver, Courtney D. DiNardo, Koji Sasaki, John A. Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B. Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N. Bhalla
MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.
{"title":"BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML","authors":"Christine E. Birdwell, Warren Fiskus, Christopher P. Mill, Tapan M. Kadia, Naval Daver, Courtney D. DiNardo, Koji Sasaki, John A. Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B. Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N. Bhalla","doi":"10.1038/s41375-025-02842-w","DOIUrl":"10.1038/s41375-025-02842-w","url":null,"abstract":"MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"304-313"},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02842-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786152","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 : 2025-12-19DOI: 10.1038/s41375-025-02819-9
Joshua N. Gustine, John A. Scaringi, Fabian Bauer, Diana D. Cirstea, Andrew R. Branagan, Benjamin R. Puliafito, Marcela V. Maus, Matthew J. Frigault, Andrew J. Yee, Umar Mahmood, Noopur S. Raje
{"title":"Prognostic value of serological and PET/CT response kinetics in patients with multiple myeloma treated with BCMA CAR-T","authors":"Joshua N. Gustine, John A. Scaringi, Fabian Bauer, Diana D. Cirstea, Andrew R. Branagan, Benjamin R. Puliafito, Marcela V. Maus, Matthew J. Frigault, Andrew J. Yee, Umar Mahmood, Noopur S. Raje","doi":"10.1038/s41375-025-02819-9","DOIUrl":"10.1038/s41375-025-02819-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"440-443"},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02819-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786154","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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