Acute Myeloid Leukemia (AML) Clinical Trial Monitor

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 About AML

What is the difference between AML and MDS?

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective hematopoiesis (dysplastic blood cell production), cytopenias (low blood counts), and an increased risk of transformation to AML. MDS is defined by <20% blasts in the marrow; once the blast count reaches ≥20%, the diagnosis becomes AML. Approximately 30% of MDS cases progress to AML over time — the rate depends on risk stratification (IPSS-R or IPSS-M score). High-risk MDS is often treated with azacitidine or decitabine, and venetoclax-based combinations are being tested in MDS as well as AML. Some clinical trials enroll both MDS and AML patients due to their overlapping biology.

What is differentiation syndrome and why does it occur with menin inhibitors and IDH inhibitors?

Differentiation syndrome (DS) is a potentially life-threatening inflammatory syndrome that occurs when targeted therapies cause rapid differentiation of large numbers of leukemic blasts — the cells mature faster than they can be cleared, releasing cytokines and accumulating in tissues. DS was first described with ATRA/ATO in acute promyelocytic leukemia (APL) and has since been observed with IDH inhibitors and menin inhibitors. Symptoms include fever, weight gain, peripheral edema, pulmonary infiltrates, pleural/pericardial effusion, and renal failure — clinically resembling capillary leak syndrome. Management includes corticosteroids, diuretics, and temporary dose interruption. Oncologists managing patients on revumenib must be vigilant for early DS signs, and routine monitoring for QTc prolongation (another revumenib side effect) is also required.

What is a KMT2A rearrangement (MLL rearrangement)?

KMT2A (lysine methyltransferase 2A, formerly called MLL or MLL1) rearrangements are chromosomal translocations that fuse the KMT2A gene at chromosome 11q23 to one of more than 80 partner genes. Common partners include AF9 (t(9;11)), AF10 (t(10;11)), ELL (t(11;19)), and AF6. KMT2A-r AML is present in ~10% of adult AML and ~20% of infant AML. The fusion protein hijacks the menin-KMT2A interaction to constitutively activate HOX gene transcription, driving leukemic stem cell maintenance. KMT2A-r AML is considered intermediate-to-high risk, with poor outcomes after standard therapy. The development of menin inhibitors was specifically motivated by understanding the mechanistic dependence of KMT2A-r AML on the menin complex.

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