The Treatment Algorithm for AML in 2025

Anand Patel, MD University of Chicago Medical Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Risk status and mutational profile are key components that guide treatment selection in both frontline and relapsed or refractory acute myeloid leukemia (AML).

• Upfront intensive chemotherapy is standard induction treatment in eligible patients, while a hypomethylating agent (HMA) plus venetoclax is standard in ineligible patients

• Targeted therapies are applicable throughout the treatment pathway, though data on combining them directly with HMA plus venetoclax regimens are still sparse.

Acute Myeloid Leukemia Introduction

Anand Patel, MD, of The University of Chicago Medical Center, joined the cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to review the current treatment algorithm for patients with AML.

Dr. Patel started by describing his center’s initial workup for AML, which includes bone marrow biopsy analysis with flow cytometry, conventional karyotyping, fluorescence in situ hybridization testing, and a broad molecular panel. These analyses determine risk stratification and molecular profile, both of which are primary drivers in therapy selection and sequencing for AML.

Treating Intensive Induction-Eligible AML

A primary distinction for newly diagnosed AML is whether a patient is eligible or ineligible for induction chemotherapy. Among patients eligible for intensive induction therapy, the standard of care is a “7+3” chemotherapy regimen. In patients with favorable-risk disease, targeted therapies like gemtuzumab or a FLT3 inhibitor can be included upfront if an actionable mutation is present. 

In patients with higher-risk disease, induction with a HMA with or without venetoclax can be an alternative to intensive chemotherapy. Dr. Patel also suggested that the treatment landscape is rapidly shifting towards greater utilization of HMA plus venetoclax regardless of fitness for intensive chemotherapy.

After induction, prior to proceeding to allogeneic transplant, patients typically receive at least one cycle of consolidation either with cytarabine-based chemotherapy or by continuing HMA plus venetoclax. Dr. Patel did cite recent data in NEJM Evidence that showed an intermediate cytarabine dose of 1.5g/m² was noninferior to the conventional 3.0g/m² dose.

In the maintenance setting for transplant-ineligible or indicated post-transplant patients, the current treatment options are indefinite oral azacitidine or a FLT3 inhibitor like midostaurin or quizartinib in patients with FLT3-mutated AML.

Upfront Therapies in Intensive Induction-Ineligible Patients

For patients with AML ineligible for intensive therapy, the standard of care induction therapy is upfront HMA plus venetoclax. Targeted therapies including ivosidenib, glasdegib, gilteritinib, enasidenib, and gemtuzumab are potential alternative treatment options based on mutation status. After induction, patients may proceed to allogeneic transplant or maintenance therapy.

Dr. Rahul Gosain asked Dr. Patel for his perspectives on triplet regimens that combine an HMA with both venetoclax and a targeted therapy. Dr. Patel personally felt that triplet combinations need more robust data on the tradeoff of increased myelosuppression for potentially better responses. Additionally, he said it’s uncertain how these regimens should be modified over time in the context of indefinite therapy. 

Dr. Rohit Gosain raised the possibility of minimal residual disease (MRD) being used to guide treatment pauses or restarts. According to Dr. Patel, while the predictive value of MRD in AML is still unclear, one retrospective analysis did find a high rate of durable remission among a cohort of patients with NPM1-mutated AML who achieved MRD-negativity and then elected to stop treatment.

Treatment Algorithm for Relapsed or Refractory AML

The doctors all emphasized that retesting the molecular profile of patients at relapse or recurrence is critical, as a number of patients acquire an actionable that was not present at baseline. If actionable mutations are found, there are several approved targeted therapies.

Giltertinib is approved for relapsed AML with FLT3-ITD or FLT3-TKD mutations. Ivosidenib and enasidenib are approved for IDH1 and IDH2 mutations, respectively, though their efficacy may be reduced in patients who have received venetoclax. Comparatively, olutasidenib, another anti-IDH1 therapy, may maintain more efficacy in venetoclax-exposed patients. Revumenib is the lead agent in the emerging class of menin inhibitors, and is effective in AML with KMT2A translocation or NMP1 mutation.

For relapsed or refractory patients without targetable mutations, the three primary options are cytarabine-based chemotherapy, HMA with or without venetoclax, and low-dose cytarabine with or without venetoclax.