Newly Diagnosed Acute Myeloid Leukemia in Unfit Patients: 2026 Treatment Algorithms

Authors

Naseema Gangat
Courtney D Dinardo

Publication Date

8-16-2025

Journal

Blood Cancer Journal

DOI

10.1038/s41408-025-01346-1

PMID

40818987

PMCID

PMC12357898

PubMedCentral® Posted Date

8-16-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Leukemia, Myeloid, Acute, Nucleophosmin, Algorithms, Disease Management, Antineoplastic Combined Chemotherapy Protocols, Acute myeloid leukaemia, Acute myeloid leukaemia

Published Open-Access

yes

Recommended Citation

Naseema Gangat and Courtney D Dinardo, "Newly Diagnosed Acute Myeloid Leukemia in Unfit Patients: 2026 Treatment Algorithms" (2025). Faculty, Staff and Student Publications. 5568.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5568