# Integrating Targeted Therapies into AML Frontline Therapy: Who Gets What and What Does the Future Hold?

## TL;DR

This review discusses how targeted therapies are changing the treatment of acute myeloid leukemia and helps clinicians decide which patients should receive which treatments.

## Contribution

The paper provides a practical guide for integrating new targeted therapies into frontline AML treatment using patient cases and current evidence.

## Key findings

- Combining targeted drugs with chemotherapy or HMA improves remission rates and survival in some AML patients.
- HMA plus venetoclax is now standard for unfit patients, offering high remission with manageable toxicity.
- FLT3 and IDH1 inhibitors are approved in combination with standard treatments, showing clinical benefit.

## Abstract

Acute myeloid leukemia is an aggressive blood cancer that, for decades, was treated with intensive chemotherapy alone, resulting in poor long-term survival for most patients due to relapse and toxicity. In recent years, a growing number of drugs targeting specific genetic changes in leukemic cells have been approved, offering more personalized treatment options. However, the rapid expansion of available therapies has created new challenges for clinicians: determining which drug is best suited for which patient, how to combine these agents with existing treatments, and how to manage their side effects. This review provides a practical guide for integrating targeted therapies into the frontline treatment of acute myeloid leukemia. Using illustrative patient cases, we discuss current evidence for each major molecular subgroup, highlight promising drug combinations under investigation, and outline strategies for treatment selection in everyday clinical practice.

For decades, induction treatment of acute myeloid leukemia consisted of intensive chemotherapy for induction. High relapse rates and severe toxicity resulted in a five-year overall survival of ~30%. In patients ineligible for intensive treatment, hypomethylating agents (HMA) could be administered but generally failed to induce durable remissions. These limitations have driven the development of targeted drugs and less toxic therapeutic regimens. In the past decade, fourteen new agents have gained FDA and/or EMA approval, including small-molecule inhibitors targeting FLT3, IDH1, IDH2, BCL-2, menin, and the hedgehog pathway, as well as a CD33-directed antibody-drug conjugate. The combination of targeted drugs with intensive chemotherapy or HMA has resulted in improved remission rates and prolonged survival in certain patient subpopulations. However, many promising combinations are currently being evaluated in randomized trials and are not yet available in clinical routine. A combination that has become standard of care is HMA plus venetoclax for patients unfit for intensive chemotherapy, achieving high remission rates with relatively manageable toxicity. Moreover, targeted drugs directed against FLT3 and IDH1 have been approved in combination with intensive chemotherapy and HMA, respectively. Clinical decision-making requires rapid molecular diagnostic testing, assessment of a patient’s fitness for intensive chemotherapy, and management of toxicities and drug interactions. This narrative review, illustrated with patient vignettes, summarizes currently available therapies, guides through the latest trials on frontline combinations in AML, and provides a preview of how the therapeutic landscape may evolve in the near future.