ASH 2025 Reveals Strategic Implications For AML Drug Development
By Jack Gordon, D.Phil., Ivo Carre, Ph.D., and Kasia Koczula, Ph.D., Lifescience Dynamics
Acute myeloid leukemia (AML) is a rare and aggressive form of blood cancer that is driven by genetic alterations in hematopoietic stem and blast cells, with an estimated 20,000 new patients per year in the U.S. and a median age at diagnosis of 68 years. Frontline treatment pathways are split according to patient age and “fitness” for intensive chemotherapy. Patients considered eligible for chemotherapy receive the “7+3” regimen of cytarabine and daunorubicin or idarubicin with the goal of reaching complete remission and stem cell transplant (HSCT). In contrast, patients ineligible for chemotherapy typically receive lower intensity regimens, such as Venclexta (venetoclax, BCL-2 inhibitor; VEN) in combination with a hypomethylating agent such as azacitidine (AZA).
Despite these well-established treatment paradigms, outcomes remain poor with five-year overall survival rates averaging ~10% for patients over 60 years old. To address these issues, clinicians have aimed to more precisely target disease-driving mutations, leading to approvals of oral small molecules targeting FLT3 and IDH mutations, which began to fragment the treatment landscape into biomarker-defined populations. AML’s transition to precision medicine has been further amplified in 2025 by the approvals of two menin inhibitors: Syndax’s Revuforj (revumenib) and Kura’s Komzifti (ziftomenib) for the ~35% of relapsed/refractory (R/R) AML patients with a mutation in NPM1. These approvals followed Revuforj’s first-in-class approval a year earlier for the estimated 4% of R/R patients with a KMT2A gene rearrangement.
Moving beyond R/R AML, ASH 2025 saw data for combinations of menin inhibitors with established treatment backbones for newly diagnosed patients: VEN/AZA for unfit patients and 7+3 chemotherapy for eligible patients. Combining menin inhibitors with these backbones may be critical to realizing their full potential, given resistance can emerge rapidly when menin inhibitors are administered alone; up to 40% of patients can gain MEN1 mutations within just two treatment cycles. While Revuforj and Komzifti show nearly identical response rates and differentiation syndrome profiles as single agents, differentiation in frontline settings may rest on safety and pharmacology. Komzifti’s lower incidence of cardiac QTc prolongation and simplified once-daily administration could make it the preferred combination partner. However, while its exceptionally long half-life (90 to 180 hours) could boost response durability, it may also demand more proactive dose management and longer washout periods compared to Revuforj, which faces its own dosing hurdles due to drug-drug interactions with commonly prescribed azole antifungals.
In unfit patients, the first data for Kura’s Komzifti combined with VEN/AZA showed promising early activity with complete remission rates (CR/CRi) of 81%. Compared to pivotal data where VEN/AZA (VIALE-A) achieved a CR/CRi rate of 67% in mNPM1 patients, the early data shows signs of additive efficacy with Komzifti, although durability and survival signals remain immature. Durability will be especially critical in mNPM1 AML, where single-agent menin inhibitor response durations have been limited, and exploratory subgroup analyses have shown a more marginal survival benefit for VEN/AZA over AZA alone. The key question will be whether menin inhibitors deepen responses beyond VEN/AZA alone or simply accelerate remissions without improving long-term disease control. Compared to other menin inhibitors being combined with VEN/AZA, Komzifti may have a slight efficacy edge, with data hinting at more responses that are negative for measurable residual disease (MRD) despite its early-stage trials being enriched for poorer-performance status patients.
In fit patients, the first data for Revuforj combined with chemotherapy was reported in a small cohort of KMT2Ar or mNPM1 patients (N=26). Here, adding Revuforj achieved deep initial responses, with 83% of patients achieving MRD-negative complete remissions, including 100% of patients at dose level 1. Notably, most patients achieved these deep responses rapidly within one treatment cycle, with a median time to MRD-negativity of around 30 days, compared to the usual two or three cycles, which could allow patients to move more quickly toward HSCT while at greater fitness and with lower disease burden while also minimizing the time at risk for infections during neutropenia.
Enzomenib: A Next-Generation Menin Inhibitor?
While Syndax’s Revuforj and Kura’s Komzifti are already approved, several other menin inhibitors are in development for AML. Of these, Sumitomo’s enzomenib gained significant attention at ASH 2025, where early data positioned it as a next-generation menin inhibitor with its lower lipophilicity and basicity resulting in faster clearance and little accumulation. At ASH 2025, updated data for enzomenib from 116 patients showed a markedly higher response rate (CR/CRh) in mNPM1 AML of 44% vs. both Revuforj and Komzifti, with no dose-limiting toxicities up to a 400 mg twice-daily dose. ASH also saw the first data for an enzomenib + VEN/AZA triplet that reported a CRc rate of 56% in R/R patients, including a 100% objective response rate in patients naïve to both Venclexta and menin inhibitors, again with no Grade ≥3 QTc prolongation or differentiation syndrome. However, enzomenib lags behind Revuforj and Komzifti, with its current data split across a range of small dose cohorts and an approval in relapsed/refractory KMT2Ar or mNPM1 AML not expected before 2027.
The Venclexta Story: A Paradigm Shift in Fit Patients
If ASH 2025 was a “menin party,” new Venclexta data proved BCL-2 inhibition can still draw a crowd. Venclexta has been the cornerstone of therapy in unfit AML patients since its accelerated approval in 2018. However, exciting data from the Phase 2 PARADIGM trial, presented as part of the plenary session, compared VEN/AZA to conventional chemotherapy in fit patients with intermediate or adverse-risk AML. Impressively, patients in the VEN/AZA arm had significantly improved event-free survival, response rates, and reduced mortality compared to patients who received chemotherapy. This represents the first U.S. head-to-head randomized data supporting the use of Venclexta-based regimens over chemotherapy in these patients, meaning even patients considered fit for chemotherapy may be better served with VEN/AZA. However, while initial data is compelling, the trial enrolled patients who were predominantly adverse-risk (72%), patients that are known to have the poorest response to chemotherapy; the bar for VEN/AZA to clear will be much higher in intermediate and favorable-risk or younger patients. Moreover, crossover to VEN/AZA by patients initially treated with chemotherapy after transplant or relapse is likely to have confounded the OS analysis, making interpreting the optimal positioning of VEN more difficult. Despite these limitations, the impact of PARADIGM is already being felt, with Syndax recently changing from plans to evaluate Revuforj with chemotherapy in fit KMT2Ar patients to investigating Revuforj with VEN/AZA in a planned RAVEN study in the same patient population.
Looking Ahead: Strategic Implications For AML Drug Development
2026 could mark a turning point in AML drug development. Biomarker fragmentation is giving way to broader access to targeted therapies, with an estimated 60% to 65% of AML patients now eligible for mutation-specific treatment following the approval of menin inhibitors for NPM1-mutated disease. As a result, differentiation within the crowded landscape of small-molecule inhibitors targeting the “big three” AML mutations (FLT3, IDH, and NPM1) is becoming increasingly difficult, pushing developers to explore novel therapeutic modalities.
One emerging strategy is targeted protein degradation. Amgen’s recent acquisition of Dark Blue Therapeutics highlights growing interest in this approach, based on the premise that eliminating oncogenic drivers, rather than inhibiting them, may overcome resistance and improve the durability of response. This shift reflects a broader recognition that incremental improvements on existing inhibitor classes may no longer be sufficient in well-served biomarker segments.
At the same time, substantial unmet need persists in high-complexity, adverse-risk AML populations, including TP53-mutated and secondary AML. In these genetically unstable subtypes, single-pathway inhibition has shown limited success. Drug developers may therefore need to pivot toward immune-based and multi-mechanistic approaches, such as CAR T or CAR NK cell therapies and bispecific antibodies, which can bypass genomic heterogeneity and engage the broader immune system.
Finally, as VEN/AZA expands into younger fit patients, the commercial and clinical opportunity is shifting toward combination-ready agents. Molecules that deliver additive or synergistic benefit alongside VEN, including MCL-1, CDK9, or NAMPT inhibitors, may offer the most viable path forward. As patient stratification evolves and VEN/AZA becomes a dominant treatment backbone, successful AML development is likely to move further away from traditional chemotherapy and toward rational, biomarker-informed combination strategies.
About The Authors:
Jack Gordon, D.Phil., is a business analyst at Lifescience Dynamics with experience delivering decision support and strategic insight projects for global pharma clients across solid and hematologic tumor indications, as well as immunology and rare diseases. His research background includes biotech preclinical R&D in areas such as neurodegeneration and expertise in computational biology and single-cell gene expression technologies.
Ivo Carre, Ph.D., is a consultant at Lifescience Dynamics in London, with a doctorate in neuroscience from the UKDRI and over two years of biopharma consulting experience. He has supported various clients across several indications, including oncology, neurology, and rare diseases, with expertise in competitive intelligence, market research, and market access.
Kasia Koczula is an engagement manager at Lifescience Dynamics, with over eight years of consulting experience in the life sciences sector. She holds a Ph.D. in hematological oncology and has worked across a broad range of therapy areas, including oncology, cardiovascular diseases, and rare diseases. Koczula specializes in competitive intelligence, market research, and strategic advisory services, supporting clients with evidence-based insights to drive informed decision-making.