Highlights in Acute Myeloid Leukemia

In this video, Dr Fabio Andreozzi, hematologist at the Institut Jules Bordet in Brussels and doctoral researcher at the laboratory of molecular biology of leukemia at the VIB-KU Leuven, provides an overview of selected highlights in acute myeloid leukemia from ASH 2025.

The summary opens with discussion of the PARADIGM study, a randomized phase II trial presented in the plenary session. This study evaluated newly diagnosed, fit AML patients who were randomized to receive either azacitidine plus venetoclax or intensive chemotherapy, consisting of either standard 7+3 or CPX-351. Patients with favorable-risk AML, FLT3-mutated disease, Philadelphia–positive AML, and mixed phenotype acute leukemia were excluded, resulting in a population largely enriched for intermediate- and adverse-risk AML. The trial demonstrated that azacitidine plus venetoclax was associated with lower rates of infection and bleeding, reduced 60-day mortality, higher response rates, and increased rates of transplantation in remission compared with intensive chemotherapy. These findings suggest a paradigm shift in the management of intermediate- and adverse-risk FLT3 wild-type AML, supporting azacitidine plus venetoclax as a preferred frontline option.¹ Future questions raised by these data include whether more intensive venetoclax-based combinations, incorporating agents such as intermediate-dose cytarabine from the first cycle, may further improve outcomes.

The CLADILLAC trial addresses relapse prevention following an allogeneic stem cell transplantation in high-risk AML patients. Building on more than a decade of work modifying the fludarabine-busulphan conditioning backbone, the MD Anderson group developed the CLADILLAC regimen to intensify conditioning while maintaining tolerability. This strategy combines fractionated myeloablative busulphan administered over 22 days with cladribine, thiotepa, venetoclax, and post-transplant cyclophosphamide. The prolonged fractionated delivery allows safe administration even in older or less fit patients. The trial enrolled 50 patients aged 18 to 70 years with high-risk AML, defined by refractory or relapsed disease, MRD positivity at first remission, secondary AML, or failure to respond to initial induction therapy. Most patients had adverse-risk disease by ELN criteria, and approximately one quarter harbored a TP53 mutation. After a median follow-up of approximately 30 months, outcomes were encouraging, with three-year progression-free survival of 58%. Patients with TP53 wild-type disease experienced particularly low relapse rates, while TP53-mutated AML remained to be associated with high relapse incidence.² These findings suggest that prolonged and intensified conditioning may substantially reduce relapse risk in selected high-risk patients, although TP53-mutated AML continues to represent a major unmet need.

A substantial portion of the AML news at ASH 2025 was dedicated to menin inhibitors. The field of menin inhibition is now moving beyond single-agent activity towards combination strategies. Updated results from the KOMET-007 trial were presented, examining ziftomenib combined with azacitidine and venetoclax in both newly diagnosed and relapsed or refractory AML. Updated data focused on newly diagnosed NPM1-mutated patients ineligible for intensive chemotherapy treated with ziftomenib, azacitidine, and venetoclax. This triplet achieved an overall response rate close to 90%, with high rates of early MRD negativity, often after only two cycles. Toxicity remained comparable to azacitidine plus venetoclax alone, with low rates of differentiation syndrome and QTc prolongation.³ More modest but still promising activity was observed in the relapsed or refractory setting, with better outcomes in NPM1-mutated compared with KMT2A-rearranged AML.⁴ These findings support the ongoing phase III KOMET-017 trial, designed to validate the addition of ziftomenib to standard backbones.

Another notable menin-based triplet was presented from the SAVE study, evaluating an entirely oral regimen of venetoclax, revumenib, and oral decitabine in newly diagnosed and relapsed or refractory AML patients unfit for intensive chemotherapy.⁵ Eligible molecular subtypes included KMT2A rearrangements, NPM1 mutations, and NUP98 rearrangements. Differentiation syndrome occurred in approximately 10% of patients but was rapidly reversible with steroids. QTc prolongation was manageable and did not necessitate treatment discontinuation. The overall response rate approached 85%, with high rates of MRD negativity, though the cohort remained small with 21 patients enrolled.⁵

Enzomenib represents a newer generation of menin inhibitors designed to minimize class-specific toxicities. Pharmacologically, the agent is characterized by rapid cellular uptake and washout. Early-phase data demonstrated low rates of differentiation syndrome and QTc prolongation, with monotherapy response rates ~40%.⁶

Combination data with azacitidine and venetoclax in relapsed or refractory NPM1-mutated and KMT2A-rearranged AML showed response rates close to 70%, with a confirmation of the favorable tolerability of enzomenib.⁷

FLT3-targeted strategies also featured prominently. Long-term results from a phase II trial combining azacitidine, venetoclax, and gilteritinib in newly diagnosed FLT3-mutated AML demonstrated complete remission rates around 90%, with 65% MRD negativity by cycle four. Three-year overall survival reached approximately 50%, with a median survival of about 30 months, exceeding historical expectations for azacitidine plus venetoclax in this population. At relapse, many patients lost the FLT3 mutation. Of note, baseline RAS mutations were associated with inferior outcomes.⁸

In the relapsed or refractory setting, a randomized study showed that adding crenolanib to salvage chemotherapy improved event-free survival and overall outcomes in FLT3-mutated AML, especially in NPM1-mutated patients and in patients proceeding to an allogeneic transplantation.⁹

Finally, several emerging therapies were highlighted, including CLN-049, a bispecific FLT3-targeting antibody with promising early safety and activity, pivekimab sunirine, an anti-CD123 antibody–drug conjugate showing high response rates in combination with azacitidine and venetoclax, and ICT01, an anti-BTN3A agent designed to activate γ9δ2 T cells and synergize with azacitidine and venetoclax.¹⁰⁻¹² Together, these studies illustrate the rapid therapeutic innovation in AML and signal continued evolution toward more effective, targeted, and combinatorial treatment strategies.