Joshua F Zeidner, Tara L Lin, Rina Li Welkie, Emily Curran, Kristin Koenig, Wendy Stock, Yazan F Madanat, Ronan Swords, Maria R Baer, William Blum, Eytan M Stein, Rebecca L Olin, Gary Schiller, Angela Nichols, Olatoyosi Odenike, Elie Traer, Curtis Lachowiez, Vu H Duong, Michael J Hochman, Sheng F Cai, Catherine Smith, Mona Stefanos, Molly Martycz, Ying Huang, Len Rosenberg, Sonja Marcus, Timothy L Chen, Ashley O Yocum, Brian J Druker, Ross L Levine, Uma Borate, John C Byrd, Alice S Mims
{"title":"阿扎胞苷、Venetoclax和Revumenib治疗新诊断的npm1突变或kmt2a重排AML。","authors":"Joshua F Zeidner, Tara L Lin, Rina Li Welkie, Emily Curran, Kristin Koenig, Wendy Stock, Yazan F Madanat, Ronan Swords, Maria R Baer, William Blum, Eytan M Stein, Rebecca L Olin, Gary Schiller, Angela Nichols, Olatoyosi Odenike, Elie Traer, Curtis Lachowiez, Vu H Duong, Michael J Hochman, Sheng F Cai, Catherine Smith, Mona Stefanos, Molly Martycz, Ying Huang, Len Rosenberg, Sonja Marcus, Timothy L Chen, Ashley O Yocum, Brian J Druker, Ross L Levine, Uma Borate, John C Byrd, Alice S Mims","doi":"10.1200/JCO-25-00914","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (<i>NPM1m</i>) or lysine methyltransferase 2A rearrangements (<i>KMT2Ar</i>).</p><p><strong>Methods: </strong>We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with <i>NPM1m</i> or <i>KMT2Ar</i> (ClinicalTrials.gov identifier: NCT03013998).</p><p><strong>Results: </strong>Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; <i>NPM1m</i>: 85.3%; <i>KMT2Ar</i>: 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; <i>NPM1m</i>: 65%; <i>KMT2Ar</i>: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.</p><p><strong>Conclusion: </strong>In older adults newly diagnosed with <i>NPM1m</i> or <i>KMT2Ar</i> AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":" ","pages":"JCO2500914"},"PeriodicalIF":41.9000,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed <i>NPM1</i>-Mutated or <i>KMT2A</i>-Rearranged AML.\",\"authors\":\"Joshua F Zeidner, Tara L Lin, Rina Li Welkie, Emily Curran, Kristin Koenig, Wendy Stock, Yazan F Madanat, Ronan Swords, Maria R Baer, William Blum, Eytan M Stein, Rebecca L Olin, Gary Schiller, Angela Nichols, Olatoyosi Odenike, Elie Traer, Curtis Lachowiez, Vu H Duong, Michael J Hochman, Sheng F Cai, Catherine Smith, Mona Stefanos, Molly Martycz, Ying Huang, Len Rosenberg, Sonja Marcus, Timothy L Chen, Ashley O Yocum, Brian J Druker, Ross L Levine, Uma Borate, John C Byrd, Alice S Mims\",\"doi\":\"10.1200/JCO-25-00914\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (<i>NPM1m</i>) or lysine methyltransferase 2A rearrangements (<i>KMT2Ar</i>).</p><p><strong>Methods: </strong>We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with <i>NPM1m</i> or <i>KMT2Ar</i> (ClinicalTrials.gov identifier: NCT03013998).</p><p><strong>Results: </strong>Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; <i>NPM1m</i>: 85.3%; <i>KMT2Ar</i>: 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; <i>NPM1m</i>: 65%; <i>KMT2Ar</i>: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.</p><p><strong>Conclusion: </strong>In older adults newly diagnosed with <i>NPM1m</i> or <i>KMT2Ar</i> AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.</p>\",\"PeriodicalId\":15384,\"journal\":{\"name\":\"Journal of Clinical Oncology\",\"volume\":\" \",\"pages\":\"JCO2500914\"},\"PeriodicalIF\":41.9000,\"publicationDate\":\"2025-06-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1200/JCO-25-00914\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1200/JCO-25-00914","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML.
Purpose: Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar).
Methods: We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with NPM1m or KMT2Ar (ClinicalTrials.gov identifier: NCT03013998).
Results: Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; NPM1m: 85.3%; KMT2Ar: 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; NPM1m: 65%; KMT2Ar: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.
Conclusion: In older adults newly diagnosed with NPM1m or KMT2Ar AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.
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The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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