{"title":"Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms","authors":"Naseema Gangat, Courtney D. Dinardo","doi":"10.1038/s41408-025-01346-1","DOIUrl":null,"url":null,"abstract":"<p>Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered <i>unfit</i> to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of <i>FLT3</i>, <i>IDH1</i>, <i>IDH2</i>, or menin for patients with <i>NPM1</i><sup>MUT</sup> or <i>KMT2A</i> rearrangements (<i>KMT2Ar</i>). Response rates (CR/CRi:40-90%) and overall survival outcomes (3-year: 0–67%) following Ven-HMA therapy are highly variable and depend primarily on tumor genetics while achievement of complete response with (CR) or without count recovery (CRi) and consolidation with allogeneic stem cell transplant (ASCT) are essential in securing long-term survival. <i>Favorable</i> genomic predictors of response to Ven-HMA include <i>NPM1</i><sup>MUT</sup>, <i>IDH2</i><sup>MUT</sup>, and <i>DDX41</i><sup>MUT</sup>, and <i>unfavorable TP53</i><sup>MUT</sup>, <i>FLT3-</i>ITD, and <i>K/NRAS</i><sup>MUT</sup>. <i>Favorable</i> predictors of overall survival include <i>IDH2</i><sup>MUT</sup>, and <i>unfavorable TP53</i><sup>MUT</sup>, <i>FLT3-</i>ITD, <i>K/NRAS</i><sup>MUT</sup>, and <i>KMT2Ar</i>. Whether or not triplet regimens provide significant survival gain over Ven-HMA in genetically targetable subgroups remains to be determined. Particularly frail patients who are considered <i>unfit</i> for Ven-HMA might benefit from monotherapy targeting <i>FLT3</i><sup>MUT</sup>, <i>IDH1/2</i><sup>MUT</sup>, <i>NPM1</i><sup>MUT</sup>or <i>KMT2Ar</i>. Future research projects should focus on incorporating patient-reported outcomes in clinical trials, optimization of Ven-HMA dosing and treatment duration especially in triplet combinations and broadening the use of ASCT and clarification of its timing.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"7 1","pages":""},"PeriodicalIF":11.6000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cancer Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41408-025-01346-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered unfit to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of FLT3, IDH1, IDH2, or menin for patients with NPM1MUT or KMT2A rearrangements (KMT2Ar). Response rates (CR/CRi:40-90%) and overall survival outcomes (3-year: 0–67%) following Ven-HMA therapy are highly variable and depend primarily on tumor genetics while achievement of complete response with (CR) or without count recovery (CRi) and consolidation with allogeneic stem cell transplant (ASCT) are essential in securing long-term survival. Favorable genomic predictors of response to Ven-HMA include NPM1MUT, IDH2MUT, and DDX41MUT, and unfavorable TP53MUT, FLT3-ITD, and K/NRASMUT. Favorable predictors of overall survival include IDH2MUT, and unfavorable TP53MUT, FLT3-ITD, K/NRASMUT, and KMT2Ar. Whether or not triplet regimens provide significant survival gain over Ven-HMA in genetically targetable subgroups remains to be determined. Particularly frail patients who are considered unfit for Ven-HMA might benefit from monotherapy targeting FLT3MUT, IDH1/2MUT, NPM1MUTor KMT2Ar. Future research projects should focus on incorporating patient-reported outcomes in clinical trials, optimization of Ven-HMA dosing and treatment duration especially in triplet combinations and broadening the use of ASCT and clarification of its timing.
期刊介绍:
Blood Cancer Journal is dedicated to publishing high-quality articles related to hematologic malignancies and related disorders. The journal welcomes submissions of original research, reviews, guidelines, and letters that are deemed to have a significant impact in the field. While the journal covers a wide range of topics, it particularly focuses on areas such as:
Preclinical studies of new compounds, especially those that provide mechanistic insights
Clinical trials and observations
Reviews related to new drugs and current management of hematologic malignancies
Novel observations related to new mutations, molecular pathways, and tumor genomics
Blood Cancer Journal offers a forum for expedited publication of novel observations regarding new mutations or altered pathways.