Acute Myeloid Leukemia Clinical Trial Landscape

Active Phase 3 AML Programs (2026)

Active Phase 2 Programs — Menin Inhibitors

Active Phase 2 Programs — VEN+AZA Combinations and FLT3

Platform / Master Protocol Trials

What Is Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is a hematologic malignancy arising from clonal expansion of immature myeloid progenitor cells (blasts) in the bone marrow. The disease is defined by ≥20% blasts in the marrow, though certain cytogenetic abnormalities qualify as AML at any blast percentage. AML is the most common acute leukemia in adults, with a median age at diagnosis of ~68 years and an annual incidence of approximately 20,000 new cases in the United States.

Unlike CLL or CML, AML is rapidly fatal without treatment — median survival without therapy is weeks to months. The disease is molecularly heterogeneous, driven by diverse somatic mutations that broadly fall into categories: (1) signaling mutations (FLT3-ITD/TKD, KIT, RAS) — drive proliferation; (2) epigenetic mutations (IDH1/2, TET2, DNMT3A, EZH2) — block differentiation; (3) transcription factor fusions (KMT2A/MLL rearrangements, RUNX1-RUNX1T1, CBF) — disrupt normal myeloid development; (4) cohesin/spliceosome/TP53 mutations — associated with high-risk or therapy-related AML.

The Menin Inhibitor Revolution

The most important mechanistic advance in AML in the last decade — possibly since the discovery of FLT3 inhibitors — is the menin inhibitor class. The key insight came from understanding how KMT2A fusions (MLL rearrangements) and mutant NPM1 maintain leukemic stem cell identity: both oncogenic programs require the menin-KMT2A protein complex to activate HOX gene transcription programs that keep cells undifferentiated.

Revumenib (Revuforj, Syndax/Sanofi) received FDA accelerated approval in November 2024 based on the AUGMENT-101 trial: 23% complete remission rate in heavily pretreated R/R KMT2A-r or NPM1-mutant AML. Approximately half of complete responders achieved undetectable MRD, enabling allogeneic transplant in some patients. Side effects include differentiation syndrome (similar to ATRA/ATO in APL) and QTc prolongation, both manageable with monitoring and dose modification.

Ziftomenib (KO-539, Kura Oncology) and bleximenib (JNJ-75276617, Janssen) are second-generation menin inhibitors in development, potentially with improved potency or selectivity. Bleximenib's Phase 3 trial (NCT06852222) is the critical next step — testing whether adding a menin inhibitor to VEN+AZA can establish a new standard of care for 40% of newly diagnosed AML patients.

IDH Inhibitors: The Earlier Generation

IDH (isocitrate dehydrogenase) mutations — IDH1 (present in ~8% of AML) and IDH2 (~12%) — were the first epigenetic targets to yield approved drugs. IDH1/2-mutant enzymes produce the oncometabolite 2-hydroxyglutarate, which inhibits TET2 and other α-ketoglutarate–dependent dioxygenases, causing epigenetic dysregulation and differentiation block. Enasidenib (Idhifa, Bristol-Myers Squibb/Servier) targets IDH2; ivosidenib (Tibsovo, Servier) targets IDH1; olutasidenib (Rezlidhia, Forma/Novo Nordisk) is a second-generation IDH1 inhibitor. All three are approved in R/R AML; ivosidenib is also approved in newly diagnosed IDH1-mutant AML with azacitidine. Like menin inhibitors, IDH inhibitors induce differentiation of leukemic blasts — a mechanism called "differentiation therapy" that is distinct from traditional cytotoxic chemotherapy.

Key Questions Driving AML Trials in 2026

• Can VEN+AZA + menin inhibitor become a standard of care? The Janssen Phase 3 bleximenib trial is the pivotal test — if positive, it would affect ~40% of newly diagnosed AML patients.
• Who benefits from intensive chemotherapy vs. VEN+AZA? In fit younger patients, is 7+3 induction still superior, or can VEN+AZA-based combinations match intensive therapy with less toxicity?
• Can MRD guide treatment decisions in AML? MRD-based discontinuation or escalation approaches (BLAST MRD, gilteritinib maintenance trials) are testing whether real-time molecular monitoring can personalize post-remission therapy.
• What to do after VEN+AZA failure? As VEN+AZA becomes standard frontline therapy, the relapsed/refractory post-VEN+AZA setting is growing — menin inhibitors, IDH inhibitors, and novel agents are the emerging options.
• How to incorporate transplant for intermediate/high-risk patients? Multiple trials are testing whether adding novel agents (venetoclax, FLT3 inhibitors, menin inhibitors) to transplant conditioning or maintenance improves outcomes.

Frequently asked questions

Related Disease Pages

• Chronic Lymphocytic Leukemia (CLL) Clinical Trials — BTK inhibitors, sonrotoclax, venetoclax
• Leukemia Clinical Trials Overview — all leukemia subtypes
• Mantle Cell Lymphoma Clinical Trials — BTK degraders, BCL-2 inhibitors
• DLBCL Clinical Trials — CAR-T, bispecific antibodies
• Non-Hodgkin Lymphoma Overview