Highlights from ASH 2025-Update in AML

December 8, 2025

The following summaries highlight key findings from research posters presented at the 67th ASH Annual Meeting, showcasing new developments in oral maintenance therapies for acute myeloid leukemia (AML).

All abstracts can be accessed here –> Abstracts ASH 2025

Selected abstracts –> Selected abstracts AML

Updated ASH Clinical Practice Guidelines on AML in Older Adults

Updated guidelines can be found here –> https://www.hematology.org/education/clinicians/guidelines-and-quality-care/clinical-practice-guidelines/acute-myeloid-leukemia-guidelines

Summary of change –> AML Summary of Changes FINAL

Key Recommendations in the ASH 2025 AML (Older Adults) Guidelines

1. Treat most older adults with AML—don’t default to supportive care only

Clinicians should offer active antileukemic treatment to most older adults at diagnosis, rather than assuming they are “too old” or “too frail” for therapy.
–> This represents a major cultural shift.

2. Use a full clinical assessment—not age alone—to guide treatment decisions

Treatment planning should consider fitness, comorbidities, symptoms, goals of care, and patient preferences.
–> Chronological age is no longer the primary determinant.

3. Lower-intensity therapy is preferred if a patient is not a candidate for intensive chemotherapy

For unfit patients, the guideline recommends hypomethylating agents (azacitidine, decitabine) or low-dose cytarabine, with or without targeted agents.
–> These approaches can offer meaningful remission with fewer side effects.

4. Molecularly targeted therapy should be used when mutations are identified

Genetic testing (FLT3, IDH1, IDH2, etc.) should guide therapy.
–> Targeted treatments improve outcomes and are now central in AML care.

5. Intensive chemotherapy remains appropriate for some older adults

For fit patients, intensive regimens (e.g., “7+3”) still have a place and may produce deeper, more durable remissions.
–> Fitness—not age—determines eligibility.

8. Consider hematopoietic stem cell transplantation (HSCT) when clinically appropriate

Transplant is no longer automatically excluded for older adults.
–> Eligibility should be assessed on biological age and overall fitness.

9. Use palliative transfusion support when antileukemic therapy is no longer pursued

For patients receiving palliative or hospice care, red blood cell transfusions and other supportive measures are recommended to improve comfort and quality of life.
–> This is a major affirmation of patient-centred end-of-life support.

10. Offer clinical trials whenever possible

Older adults should have expanded access to trials, and clinicians should actively seek enrollment opportunities.
–> ASH stresses that older adults remain underrepresented in AML research.

11. Shared decision-making should guide treatment choices

Clinicians and patients should work together to balance risks, benefits, logistics, and goals of care.
–> This elevates patient autonomy and quality of life in therapy decisions.

What These Recommendations Mean for Advocacy

More older patients will now be offered real treatment options, not just supportive care.
Genomic testing becomes essential, not optional, for equitable care.
Targeted therapies and lower-intensity regimens will expand access to effective treatments.
Quality-of-life and palliative care are now formally included in AML best practice.

A less-intensive treatment that may improve outcomes in AML1

Fathi AT, et al. 2025;146(Suppl 1):6.

What was the study about?

Standard treatment for AML has long been intensive chemotherapy, but it often causes serious side effects and long-term outcomes remain poor. A recent drug combination, azacitidine plus venetoclax (aza-ven), has shown strong results in people with AML who cannot tolerate intensive chemotherapy.

Venetoclax is a targeted cancer medicine that blocks a protein called BCL-2. BCL-2 helps leukemia cells survive. By turning off this protein, venetoclax helps destroy cancer cells.

This study looked at whether aza‑ven could replace standard intensive chemotherapy as the first treatment for adults with AML who can tolerate full‑dose, intensive chemotherapy.

Who took part?

172 people with newly diagnosed AML
People were randomly and evenly split between the treatment groups

- 86 received aza-ven, average age 65 years
- 86 received standard intensive chemotherapy, average age 64 years

Key results

The study met its main goal, showing that aza-ven provided significant benefits over intensive chemotherapy:

Event-free survival: After 1 year, 53% of people on aza-ven were living without relapse, disease progression, or death, compared with 36% on intensive chemotherapy
Complete remission: After nearly 2 years, 56% of people treated with aza-ven had less than 5% cancer cells in their blood or bone marrow, compared with 49% of people on intensive chemotherapy
Response to treatment: After nearly 2 years, 88% of people treated with aza-ven responded to treatment, compared with 62% on intensive chemotherapy. Among those who responded, more people on aza-ven were able to go on to a bone marrow transplant compared with those on standard chemotherapy (52 vs 34 participants)
Overall survival: The time that people stayed alive on treatment was similar between the two groups. On average, half of people on aza-ven were still alive at 21.5 months compared with 18.6 months for those who received intensive chemotherapy

Key safety information

Low blood counts were common and occurred at similar rates with both treatments
Serious lung infections and sepsis were slightly less frequent with aza‑ven than with intensive chemotherapy
No one on aza-ven died within the first 60 days compared with 4 patients on intensive chemotherapy

Quality of life and time in hospital

After 2 weeks of treatment, people on aza-ven reported a better quality of life and had fewer depressive symptoms than those on intensive chemotherapy, but these differences did not continue in the long term
People on aza-ven spent significantly less time in the hospital during the first 6 months, and no one on aza-ven needed intensive care unit treatment in the first 30 days, compared with nearly 10% on intensive chemotherapy

What does this study mean for people with AML?

For people with AML who are eligible for intensive chemotherapy, aza-ven offers an alternative treatment option that may enable shorter hospital stays, better quality of life, and strong treatment responses.

Key highlights

Overall Clinical Insights

Targeted therapy integration (FLT3, IDH1, BCR-ABL, menin, bispecific antibodies) is reshaping both frontline and relapsed AML treatment.
Venetoclax-based regimens continue to expand into all AML settings—with some combinations showing potential to replace intensive induction in selected adults.
Menin inhibitors are the new frontier for NPM1-mutated and KMT2A-rearranged AML, though resistance remains challenging.
Pediatric AML is moving toward less intensive, risk-adapted therapy while maintaining excellent outcomes.
Transplant outcomes are improving through optimized conditioning, better donor selection, and novel maintenance strategies.
MRD is now validated as a robust surrogate endpoint for AML trials.
Outcomes across decades continue to improve, reflecting major advancements in biomarker-driven therapy, supportive care, and transplant practice

Frontline Therapy Advances in Newly Diagnosed AML

Targeted + Intensive Chemotherapy

Adding TKIs (e.g., for BCR::ABL1+ AML) or IDH1 inhibitors (ivosidenib) to intensive chemotherapy improves response rates and overall outcomes in newly diagnosed AML.
Menin inhibitors (revumenib, enzomenib, ziftomenib) combined with standard low-intensity regimens (AZA + VEN) show promising efficacy, especially for NPM1-mutated and KMT2A-rearranged AML.
Updated data from large registries (e.g., PETHEMA, French intergroup) show that the last three decades have produced progressive survival improvements, likely due to targeted agents, better supportive care, and improved transplant practices.

Low-Intensity Regimens for Unfit or Older Patients

Venetoclax-based regimens (VEN+AZA; VEN+AZA+gilteritinib) continue to deliver high remission rates and are being explored as primary therapy even in fit older adults, where randomized trials compare them directly with intensive chemotherapy.
Novel combinations such as pivekimab sunirine + VEN/AZA or γ9δ2 T-cell activation (ICT01) + Aza-Ven show high remission and survival signals in early trials.

Targeted Therapy in Relapsed/Refractory AML

Menin inhibitors (enzomenib, revumenib): Monotherapy shows limited OS in relapsed/refractory AML; combination with venetoclax + azacitidine improves responses.
FLT3-mutated AML: Gilteritinib post-HCT, CLIA + FLT3 inhibitors, and crenolanib improve outcomes in relapsed/refractory patients.
IDH1-mutated AML: Ivosidenib combined with intensive chemotherapy or as maintenance therapy shows encouraging efficacy.
Tyrosine kinase inhibitors (BCR::ABL1+ AML): Adding TKI to intensive chemotherapy improves survival

Clinical Implications:

Targeted agents are essential for molecularly defined subgroups.
Combining targeted therapy with HMAs or intensive chemo may improve outcomes in relapsed/refractory AML.

Targeted Therapy in Molecularly Defined Populations

FLT3-mutated AML

Post-hoc analyses of ADMIRAL/COMMODORE and other trials show:
- Gilteritinib can be re-started post-HSCT with meaningful responses.
- Sequential gilteritinib after MEC, and CLAG-Ven or CLAG-Gilt combinations, show encouraging activity for R/R FLT3-mutated AML.
- Long-term follow-up suggests sustained benefit of VEN+AZA+gilteritinib frontline combinations.
Crenolanib combined with salvage chemotherapy improves outcomes in FLT3-mutant, NPM1 co-mutated R/R AML.

Menin/KMT2A/NPM1-mutant AML

Menin inhibitors (revumenib, enzomenib, ziftomenib) as monotherapy or in combination with VEN/AZA demonstrate:
- High response rates, especially in KMT2A-r and NPM1-mutated AML.
- Some resistance issues—patients relapsed/refractory to menin inhibitors have poor outcomes.

Anti-FLT3 x CD3 bispecific antibodies

CLN-049 shows preliminary anti-leukemia activity in R/R AML/MDS.

Pediatric AML Therapy Optimization

Studies from COG (AAML1831, MyeChild01) support several shifts:

Etoposide can be removed from induction without harming survival.
Optimized low-risk strategies reduce therapy intensity while preserving excellent outcomes.
High-dose cytarabine consolidation is not improved by adding fludarabine.
Real-world analyses highlight racial/ethnic disparities in relapse survival.
Venetoclax-based regimens show activity in pediatric AML and therapy-related myeloid diseases.

Venetoclax: Across Lines, Ages, and Risk Groups

Across multiple trials

Fit and unfit adults: Venetoclax + azacitidine/cytarabine shows high response rates and durable remissions

VEN-based therapies continue to demonstrate strong remission rates in first-line older adults, R/R AML, and molecular subgroups.
Randomized trials comparing Venetoclax + azacitidine vs. conventional induction indicate potential non-inferiority in fit adults.
VEN combinations with CLAG or CLAG-GO regimens show promise in R/R AML.
Novel combinations: Venetoclax + gilteritinib, pivekimab sunirine + venetoclax + azacitidine, and selinexor + venetoclax + azacitidine show promising early results.
Shortened venetoclax courses in real-world practice retain efficacy

Clinical Implications:

Venetoclax combinations are becoming standard for older/unfit adults and select pediatric patients.
Combinations with targeted therapy and immunotherapy may further improve survival.

Immunotherapy & Cellular Approaches

γ9δ2 T-cell activation (ICT01) + azacitidine-venetoclax shows high remission rates.
Radiopharmaceutical therapy (90Y-antiCD25) and Orca-T engineered cell therapy explored post-HCT.

Clinical Implications:

Cellular immunotherapy may complement standard AML therapy, especially in relapsed/refractory disease.
Novel immunotherapeutic approaches could become part of transplant or post-transplant strategies.

Chemotherapy Optimization

Induction chemotherapy: Single anthracycline cycle in younger adults is sufficient (BIG-1).
Pediatrics: Etoposide can be removed safely; high-dose cytarabine not superior to fludarabine + cytarabine consolidation.
CLAG-GO and CLIA regimens combined with venetoclax show efficacy in relapsed/refractory AML

Clinical Implications:

Chemotherapy intensity can be reduced in selected populations without compromising efficacy.
Optimization allows safer integration of targeted therapies.

Treatment in Special Subgroups

Therapy-Related AML

CBF therapy-related AML studies highlight distinct biology and outcomes, with potential for targeted improvement.

DDX41-mutated AML

Outcomes differ significantly between frontline HMA/VEN vs. intensive chemotherapy, helping define optimal management.

11q23/KMT2A-rearranged AML

Large consortium analysis characterizes clinical patterns and prognostic features.

Real-world and registry data

Older FLT3-mutated AML and DDX41-mutated AML cohorts reinforce evolving treatment patterns.

Transplantation and Conditioning Innovations

Conditioning Regimens

Several studies evaluate adjustments to conditioning:

Hypomethylating agent + venetoclax induction yields similar post-HCT survival to intensive chemotherapy

- Fludarabine/melphalan yields superior long-term outcomes in older AML/MDS.
- Thiotepa addition to busulfan regimens does not improve survival.
- Novel Cladillac (Bu/Flu/Cladribine/Thiotepa/Venetoclax) regimen shows activity in high-risk AML.
- First-in-human anti-CD25 radiopharmaceutical therapy with TMLI demonstrates feasibility.

Donor Sources and GvHD Prophylaxis

Studies comparing:
- Haploidentical vs matched unrelated donors with PTCy prophylaxis.
- Haploidentical vs mismatched unrelated donor HCT for secondary AML.
- Orca-T regulatory T-cell engineered grafts reduce GvHD risk.

Maintenance Therapy Post-HCT

ONC201 and FLT3 inhibitor maintenance strategies show early evidence of benefit in reducing relapse

Clinical Implications:

HCT remains crucial for high-risk AML, but conditioning intensity can be individualized.
Post-HCT targeted maintenance is increasingly important to prevent relapse.

Measurable Residual Disease (MRD), Prognostic Modeling and real world insights

The HARMONY Alliance validates MRD as a surrogate endpoint for survival in AML clinical trials.
PRISM integrates clinical and molecular features to model survival in newly diagnosed AML treated with venetoclex-based therapy, enabling more precise prognostication.
Real-world factors: Obesity, age, and genetic mutations (DDX41) impact outcomes; shortened therapy courses can be effective.
Long-term registry data (PETHEMA): Shows significant improvement in AML outcomes over three decades.

Clinical Implications: