Best of Heme 2025: Advances in Acute Myeloid Leukemia (AML) with Dr Naval Daver
Presented by:
Naval Daver, MD | MD Anderson Cancer Center
Conference:
Best of Heme 2025 | Vail, Colorado
Introduction
At the 2025 Best of Heme conference in Vail Colorado, Dr. Naval Daver began his presentation with an optimistic outlook on treatment advances in acute myeloid leukemia: "AML has been catching up with myeloma and lymphoma in drug approvals. This has already led to improvements in survival, especially in patients with targetable mutations such as FLT3 and IDH." Dr Daver noted that, while AML remains a complex and heterogeneous disease, recent breakthroughs in targeted therapies have transformed treatment paradigms in the frontline and relapsed/refractory (R/R) setting. Dr Daver emphasized that FLT3 inhibitors, IDH inhibitors, and Menin inhibitors have driven the bulk of progress, and that combination therapies will be key to overcoming treatment resistance and improving long-term survival.
FLT3-Mutated AML: The Role of FLT3 Inhibitors
Dr Daver noted that "FLT3 inhibitors have played a crucial role in improving outcomes in AML… But single-agent response rates and response durability are suboptimal – combination strategies are needed to optimize the survival benefits of these targeted therapies." He noted some of the key FLT3 inhibitors and their evolution over time, with first generation FLT3-inhibitors such as midostaurin showing efficacy in the frontline RATIFY trial, second-generation FLT3 inhibitors like gilteritinib showing efficacy in the R/R setting in the ADMIRAL trial, and quizartinib, showing efficacy in combination with intensive chemotherapy, in the QUANTUM-First frontline trial.
Frontline Combinations in FLT3+ AML
Dr Daver also noted the impact of frontline combination therapies, such as quizartinib + 7+3 chemo in the QUANTUM-First Trial, which showed a 4-year overall survival (OS) rate of 60% in patients with newly diagnosed FLT3-ITD AML under the age of 60. He also noted that quizartinib demonstrated an especially significant survival benefit in patients with NPM1, DNMT3A, or TET2 co-mutations. As an alternative strategy for older patients, Dr Daver also cited the combination of Azacitidine + Venetoclax (AZA-VEN) + FLT3 Inhibitors; for example, the AZA-VEN-Gilteritinib combination showed a 95% CR+CRi rate, with overall better tolerability, when used in elderly patients.
"For patients over 60, intensive chemo is often too toxic. Low-intensity regimens like AZA-VEN + FLT3 inhibitors are emerging as the new standard with high efficacy, better tolerability, and manageable myelosuppression with optimal dose modifications."
Post-Remission Maintenance & MRD-Guided Therapy
In the post-remission setting, Dr Daver reviewed the use of minimal residual disease (MRD) to guide therapy, and findings from the MORPHO Trial, which showed that gilteritinib maintenance therapy improved event-free survival (EFS) in MRD-positive FLT3-AML post-allogeneic stem cell transplant (ASCT). He further noted that MRD testing using NGS (Next-Generation Sequencing) is critical in FLT3-mutated AML for guiding transplant decisions.
"We may reach a point as the data grows where we are able to identify certain MRD-negative patients who don’t require transplant in CR1 – but for now, we are still recommending transplant in all FLT3-ITD patients in CR1, when feasible."
Menin Inhibitors for KMT2A and NPM1-Mutated AML
Dr Daver reviewed the use of menin inhibitors for patients with KMT2A and NPM1-Mutated AML, noting that KMT2A-rearranged AML (MLLr) has historically dismal outcomes, with a median OS of <4.0 months for patients with R/R disease. In addition, Dr Daver noted that NPM1-mutated AML, while favorable in newly diagnosed cases, has poor outcomes in the setting of relapsed disease, similar to outcomes in non NPM1-mutated R/R AML: "Relapsed NPM1-mutated AML is NOT a favorable disease. We must treat it aggressively and need new and effective agents, just like KMT2A-rearranged AML."
Dr Daver noted emerging drugs in the menin inhibitor drug pipeline in his presentation, including Revumenib (SNDX-5613), which was FDA approved in October 2024 for R/R KMT2A-rearranged AML, as well as Bleximenib and Enzomenib, two new agents which have shown early promise. Dr Daver also cited combination strategies utilizing the menin inhibitors, such as Revumenib + Venetoclax + Azacitidine ("SAVE" regimen), which has shown an 88% overall response rate (ORR) in patients with R/R AML, with 46% of patients showing a complete response (CR); he noted the strategy as being potentially superior to single-agent therapy: "Single-agent activity is good, but combinations will be essential. The goal is to move Menin inhibitors into frontline settings in optimally dose modified effective and safe combinations."
IDH-Mutated AML: Expanding the Treatment Toolbox
For patients with IDH-mutated AML, Dr Daver highlighted efforts to improve the range of therapies, including the first FDA-approved targeted IDH1/2 Inhibitors Ivosidenib (targeting IDH1) and Enasidenib (targeting IDH2), as well as a newer (more recently FDA approved) agents with promising efficacy and potentially longer durability, Olutasidenib (targeting IDH1). He also noted the use of Triplet Therapy in IDH-Mutated AML, with regimens such as Azacitidine + Venetoclax + Ivosidenib ("AZA-VEN-IDH"). This combination has shown 3-year OS rates of 90% in newly diagnosed IDH-mutated AML not eligible for intensive chemotherapy, with superior OS compared with AZA-VEN alone as observed in early clinical trials.
"Triplet therapy is proving to be the way forward for IDH-mutated AML, with unprecedented survival rates in frontline IDH mutated AML."
Unmet Needs: TP53-Mutated AML and Future Immunotherapy Approaches
Commenting on the future directions in ALL and current unmet needs, Dr Daver noted that TP53-Mutated AML remains a major challenge for clinicians, with a median OS of <6 months for patients in the R/R setting, even with the use of novel therapies. Some recent investigational approaches in this area included major efforts with APR-246 (Eprenetapopt), a TP53 reactivator, and Magrolimab, a CD47-blocking macrophage checkpoint inhibitor, which unfortunately did not meet success in the respective phase II registration studies. He also noted the ‘next wave’ of likely breakthroughs in this extremely difficult to treat subset may be using immunotherapy in AML, including the bispecific antibodies (CD123/CD3, FLT3/CD3), CAR-T & NK Cell-directed Therapies for AML, as well as macrophage checkpoint inhibitors (CD47, SiRPa, or CLEVER-1 targeting agents).
"TP53-mutated AML remains our biggest challenge in AML and MDS. Most targeted therapies have failed, but immunotherapies may hold promise and the amount of preclinical, clinical, and translational research in this subset is unprecedented.."
Summary and Key Takeaways
✔ In FLT3-mutated AML, Dr Daver noted agents like quizartinib and gilteritinib which are improving survival, especially in combination with chemotherapy or AZA-VEN in the frontline setting. MRD-directed therapy may also be important in the future.
✔ On the topic of Menin inhibitors, Dr Daver noted that FDA approval of Revumenib marks a new era for KMT2A and NPM1-mutated AML, and that combination therapies, especially in the frontline setting, will be crucial to harness maximal impact of these agents.
✔ For IDH-mutated AML, Dr Daver noted the impact of triplet therapy (AZA-VEN-IDH), which may be redefining the standard of care, with 3-year survival rates nearing 90%.
✔ For TP53-mutated AML, Dr Daver cited the ongoing unmet need in this area, the tremendous redoubled research efforts in this field, and that immunotherapies may offer hope in future trials.
✔Dr Daver noted that the future of AML treatment will rely on personalized, genomics-driven approaches, with combination regimens tailored to specific molecular subtypes.
“We have come a long way in AML therapy, but there is still much work to be done. Combination therapies and MRD-guided treatment strategies will shape the future.”
Speaker Disclosure Information: Dr Daver has received research funding from Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Gilead Sciences, ImmunoGen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi Pharm, Fate Therapeutics, Amgen, Kite Pharma, Novartis, Astex Pharmaceuticals, KAHR, Shattuck, Sobi, GlycoMimetics, and Trillium; has been an advisor for Astellas Pharma, AbbVie, Genentech, Daiichi Sankyo, Novartis, Jazz Pharmaceuticals, Amgen, Servier, Karyopharm Therapeutics, Trovagene, Trillium, Syndax, Gilead Sciences, Pfizer, Bristol Myers Squibb, Kite Pharma, Actinium Pharmaceuticals, Arog Pharmaceuticals, ImmunoGen, Arcellx, and Shattuck.
You can see the full presentation from the 2025 Best of Heme conference here, with Dr Daver’s presentation beginning at the 39:21 mark.