An international study led by the University of Colorado Cancer Center has uncovered why venetoclax-based therapy, the most common treatment for newly diagnosed acute myeloid leukemia (AML), fails in certain patients. The research, published in Blood Cancer Discovery, analyzed data from 678 AML patients—the largest cohort studied to date for this treatment—and identified key factors that determine treatment response.
The study found that both gene mutations and the maturity of leukemia cells significantly affect how patients respond to the drug combination of venetoclax and hypomethylating agents (HMA). This dual-factor approach provides new insights into treatment resistance mechanisms that could transform how doctors select therapies for AML patients.
Monocytic AML Subtype Shows Poor Treatment Response
Researchers discovered that patients with monocytic AML, a specific subtype of the disease, experienced worse outcomes, particularly when they lacked the NPM1 gene mutation. These patients were nearly twice as likely to die from the disease compared to other patient groups, according to Daniel Pollyea, MD, MS, professor of medicine at the CU School of Medicine.
"Patients with monocytic AML and no NPM1 mutation were nearly twice as likely to die from the disease," Pollyea explained. "So, it's not just about the gene mutations. It's also about how developed or mature the cancer cells are when treatment begins."
The study also revealed that patients with monocytic AML were more likely to carry additional mutations, such as KRAS, that are associated with drug resistance. This finding suggests that multiple resistance mechanisms may operate simultaneously in certain patient populations.
Novel Approach Combines Genetic and Cellular Factors
Unlike previous research that typically focused on either genetic mutations or cell type in isolation, Pollyea's team examined both factors together. This comprehensive approach provided a clearer understanding of how genetic and cellular characteristics interact to influence treatment response.
"We learned that some cancer cells basically find a back door to evade the treatment," Pollyea said. "By identifying how and why that happens, we can begin designing therapies that shut down those escape routes."
The research addresses a critical clinical need, as AML primarily affects older adults who often cannot tolerate traditional chemotherapy. Venetoclax plus HMA has improved survival for many patients, but treatment failure and relapse remain significant challenges.
Implications for Personalized AML Treatment
The findings offer doctors a powerful new risk classification system that could improve treatment selection from the start of therapy. By analyzing both genetic mutations and cell maturity, clinicians may be able to better predict which patients are likely to respond to venetoclax-based treatment and which might benefit from alternative approaches.
"This is a major step toward personalized medicine in AML," Pollyea noted. "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 and ultimately improve survival rates."
The research team is now working to expand the study with additional patient data and plans to design a clinical trial that uses this predictive model to guide treatment decisions. The study involved collaboration with multiple international institutions, including the Knight Cancer Institute at Oregon Health and Science University, several French medical centers, and the University of North Carolina's Lineberger Comprehensive Cancer Center.
