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| Ref Type | Journal Article | ||||||||||||
| PMID | (40504618) | ||||||||||||
| Authors | Zeidner JF, Lin TL, Welkie RL, Curran E, Koenig K, Stock W, Madanat YF, Swords R, Baer MR, Blum W, Stein EM, Olin RL, Schiller G, Nichols A, Odenike O, Traer E, Lachowiez C, Duong VH, Hochman MJ, Cai SF, Smith C, Stefanos M, Martycz M, Huang Y, Rosenberg L, Marcus S, Chen TL, Yocum AO, Druker BJ, Levine RL, Borate U, Byrd JC, Mims AS | ||||||||||||
| Title | Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML. | ||||||||||||
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| Abstract Text | 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).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).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.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. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| KMT2A rearrange | acute myeloid leukemia | sensitive | Azacitidine + Revumenib + Venetoclax | Phase I | Actionable | In a Phase I trial, combination of Vidaza (azacitidine), Veclexta (venetoclax), and Revuforj (revumenib) led to an overall response rate (ORR) of 88.4% (38/43), complete response (CR) rate of 67.4%, composite CR (CRc) rate of 81.4%, and median overall survival of 15.5 mo in older adults with newly diagnosed acute myeloid leukemia harboring KMT2A rearrangements (KMT2Ar) or NPM1 mutations, ORR, CR, and CRc rates were 100%, 78%, and 89% in KMT2Ar (n=9) (PMID: 40504618; NCT03013998). | 40504618 |