Why AML Treatments Don’t Always Work—and What This Study Reveals About KRAS, NPM1, and Monocytic Resistance
- Terri Conneran KRAS Kickers
- May 22
- 2 min read
Updated: Jun 5
By KRAS Kickers – Cancer Knowledge + Research + Advocacy = Survivorship
📅 May 2025 | 🧬 Published in Blood Cancer Discovery
🔬 Research led by Dr. Daniel Pollyea, University of Colorado Anschutz Medical Campus
💡 At a Glance
A major new study may explain why some patients with acute myeloid leukemia (AML) respond well to the widely used drug combination of venetoclax + hypomethylating agents (HMAs)—while others don’t. The study analyzed 678 patients (the largest group of its kind) and uncovered two crucial factors:
✅ Your gene mutations (such as KRAS, TP53, and NPM1)✅ How mature your leukemia cells are (a feature known as their phenotype)
“We’re moving closer to a world where we can look at a patient’s leukemia on day one and know which therapy gives them the best chance,”— Dr. Daniel Pollyea
🔬 The GEN-PHEN-VEN Study: What It Found
Researchers studied how genetic and phenotypic (cell-type) differences influence AML response to venetoclax + HMA. The project, called GEN-PHEN-VEN, combined:
Mutation analysis (genotype)
Cell differentiation level (phenotype)
🧫 Key Findings:
Patients with monocytic AML had significantly worse outcomes, especially if they lacked an NPM1 mutation.
Certain mutations—KRAS, NRAS, FLT3-ITD, TP53—were strongly tied to resistance.
Cancer cells that are more mature often evade venetoclax by relying on alternative survival pathways like MCL-1, not BCL-2.
“Some cancer cells basically find a back door to evade the treatment. Now we’re learning how to shut those escape routes,” — Dr. Pollyea
🧭 What This Means for AML Patients
For patients with KRAS or TP53 mutations—or those with monocytic cell types without NPM1—this research explains why standard therapies may fall short. More importantly, it helps guide what to do next:
✅ Ask for comprehensive biomarker testing.
✅ Inquire about the phenotype (monocytic vs primitive AML).
✅ Explore clinical trials for high-risk mutations or resistance patterns.
The study also supports more personalized treatment decisions. Rather than trial and error, doctors may soon use this genetic/phenotypic model to choose the right therapy from day one.
🔎 Table: Risk Markers & Treatment Implications
Marker | Treatment Insight |
NPM1+ | Predicts better response to venetoclax |
Monocytic AML | Associated with resistance (esp. NPM1–) |
KRAS/NRAS | Tied to venetoclax resistance |
TP53 | Known poor-risk mutation |
FLT3-ITD | Aggressive subtype, potential resistance |
🧠 For Researchers and Oncologists
The GEN-PHEN-VEN study emphasizes a dual approach for AML classification—genomic and phenotypic. This new risk stratification tool offers better precision when determining if venetoclax is likely to work or whether alternatives are needed.
“Understanding both the genetic and phenotypic landscape of AML is crucial. It allows for a more tailored therapeutic approach and ultimately improves outcomes.”— Dr. Daniel Pollyea
This study lays the groundwork for future trials that match treatment to patient biology, not just broad subtypes.
KRAS Kickers Takeaway
This study reinforces why KRAS Kickers pushes for:
Earlier and more comprehensive testing
Treatment personalization
Knowledge-sharing between patients and providers
We call this Gen-Me Medicine—where treatment is guided by your biology and your mutation.
You’re a person, not a statistic—survival is strategic.
Be empowered & strategic!
📖 Learn More
🧬 Full study in Blood Cancer Discovery:Genetic and Phenotypic Correlates of Clinical Outcomes in AML
📰 Summary from EurekAlert:Read the News Release
News Release 21-May-2025
