Management of Acute Myeloid Leukemia: A Review

TL;DR

This review discusses new drug strategies for treating acute myeloid leukemia, focusing on genetic subtypes and highlighting progress and remaining challenges.

Contribution

The paper provides an updated overview of targeted therapies for AML, emphasizing novel agents and their efficacy in molecularly defined subtypes.

Findings

Menin inhibitors show significant activity in NPM1-mutated and KMT2A-rearranged AML.

FLT3 inhibitors improve survival in FLT3-mutated AML, with potential benefits in FLT3–wild-type disease.

TP53-mutated AML remains a therapeutic challenge despite some initial response to hypomethylating agents and venetoclax.

Abstract

Acute myeloid leukemia is a life-threatening blood cancer with many treatment options, but outcomes vary depending on a person’s age and the genetic changes in their cancer cells. While some new therapies have improved remission rates and survival, certain subtypes of leukemia, for example those with TP53 mutations, remain difficult to treat. This review explores new drug strategies being studied in clinical trials, including therapies that target specific mutations, such as NPM1, KMT2A, FLT3 and IDH1/2, as well as early research into overcoming resistance in TP53-mutated leukemia. The goal is to highlight how these emerging therapies are reshaping treatment approaches and to identify where research is still urgently needed. By summarizing the latest progress and challenges, this work aims to guide future research and improve outcomes for patients with this complex and deadly disease.

Background/Objectives: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with historically poor outcomes, particularly among older adults and patients harboring high-risk molecular features. Advances in genomic profiling have enabled the development of targeted therapies, reshaping treatment algorithms beyond conventional cytarabine-anthracycline induction and hypomethylating agent-based regimens. This review summarizes current evidence and emerging therapeutic strategies across four evolving areas: menin inhibition, FLT3 inhibition, IDH inhibition and treatment approaches for TP53-mutated AML. Methods: We reviewed published clinical trials, preclinical studies, and ongoing clinical trials evaluating targeted therapies in AML. Emphasis was placed on agents with regulatory approval or substantial clinical development, including menin inhibitors, FLT3 inhibitors, IDH inhibitors and novel therapies directed at TP53-mutated disease. Mechanistic data, response rates, survival outcomes, and resistance patterns were analyzed to provide an updated overview of therapeutic progress. Results: Menin inhibitors have demonstrated significant activity in NPM1-mutated and KMT2A-rearranged AML, with agents such as revumenib and ziftomenib producing meaningful remission rates and ongoing studies exploring combination strategies to mitigate resistance. FLT3 inhibitors, including midostaurin, gilteritinib, and quizartinib, have improved survival in FLT3-mutated AML, while emerging evidence supports potential benefit in selected FLT3–wild-type disease based on FLT3-like gene expression signatures. IDH inhibitors, namely ivosidenib and enasidenib, have provided increased efficacy in AML patients carrying these mutations. Questions still remain regarding their efficacy in contrast to venetoclax which has been shown to be particularly effective against this population. In contrast, TP53-mutated AML remains a therapeutic challenge: although hypomethylating-agent/venetoclax-based regimens yield improved initial responses, remissions are generally short-lived and overall survival remains poor. Early-phase therapies, including p53 reactivators and multi-kinase inhibitors, show preclinical promise but lack definitive clinical efficacy to date. Conclusions: Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets.

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