Gene mutations and cell maturity identified as key factors in acute myeloid leukemia treatment resistance

An international study led by the University of Colorado Cancer Center has uncovered why a widely used treatment for acute myeloid leukemia (AML) doesn’t work for everyone. The findings could help doctors better match patients with the therapies most likely to work for them.

The study was published today in Blood Cancer Discovery.

Researchers analyzed data from 678 AML patients, the largest group studied to date for this treatment and found that both gene mutations and the maturity of leukemia cells affect how patients respond to a drug combination of venetoclax and hypomethylating agents (HMA).

“Venetoclax-based therapies are now the most common treatment for newly diagnosed AML,” said Daniel Pollyea, MD, MS, professor of medicine at the CU School of Medicine on the University of Colorado Anschutz Medical Campus. “But not all patients respond the same way. Our goal was to figure out why and give doctors better tools to predict outcomes at the start.”

AML is a fast-growing cancer of the blood and bone marrow, most often seen in older adults. Many patients can’t tolerate traditional chemotherapy, so doctors treat them with venetoclax plus HMA. This combination has improved survival for many, but some patients still relapse or don’t respond.

The study found that patients with a certain type of AML, called “monocytic,” had worse outcomes especially if they did not have a helpful gene mutation known as NPM1. These patients were also more likely to carry other mutations, such as KRAS, that are linked to drug resistance.

“Patients with monocytic AML and no NPM1 mutation were nearly twice as likely to die from the disease,” said Pollyea. “So, it’s not just about the gene mutations, it’s also about how developed or mature the cancer cells are when treatment begins.”

Previous research often focused only on either genetic mutations or cell type. Pollyea’s team looked at both, giving them a clearer understanding of how these two factors work together to influence treatment response.

“We learned that some cancer cells basically find a back door to evade the treatment,” said Pollyea. “By identifying how and why that happens, we can begin designing therapies that shut down those escape routes.”

For doctors, this research offers a powerful new way to classify AML patients by risk, meaning they can better predict who is likely to respond to venetoclax and who might need another approach.

“This is a major step toward personalized medicine in AML,” said Pollyea. “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.”

Pollyea and his team are working to expand the study with even more patient data and hope to design a clinical trial that uses this model to guide treatment decisions.

Other institutions that contributed to the study include the Knight Cancer Institute at Oregon Health and Science University; Hôpital Lyon Sud in Pierre-Bénite, France; CHU Clermont-Ferrand, France; Saint Priesten in Jarez, France; and the Lineberger Comprehensive Cancer Center at the University of North Carolina.

An international study led by the University of Colorado Cancer Center has uncovered why a widely used treatment for acute myeloid leukemia (AML) doesn’t work for everyone. The findings could help doctors better match patients with the therapies most likely to work for them.

The study was published today in Blood Cancer Discovery.

Researchers analyzed data from 678 AML patients, the largest group studied to date for this treatment and found that both gene mutations and the maturity of leukemia cells affect how patients respond to a drug combination of venetoclax and hypomethylating agents (HMA).

“Venetoclax-based therapies are now the most common treatment for newly diagnosed AML,” said Daniel Pollyea, MD, MS, professor of medicine at the CU School of Medicine on the University of Colorado Anschutz Medical Campus. “But not all patients respond the same way. Our goal was to figure out why and give doctors better tools to predict outcomes at the start.”

AML is a fast-growing cancer of the blood and bone marrow, most often seen in older adults. Many patients can’t tolerate traditional chemotherapy, so doctors treat them with venetoclax plus HMA. This combination has improved survival for many, but some patients still relapse or don’t respond.

The study found that patients with a certain type of AML, called “monocytic,” had worse outcomes especially if they did not have a helpful gene mutation known as NPM1. These patients were also more likely to carry other mutations, such as KRAS, that are linked to drug resistance.

“Patients with monocytic AML and no NPM1 mutation were nearly twice as likely to die from the disease,” said Pollyea. “So, it’s not just about the gene mutations, it’s also about how developed or mature the cancer cells are when treatment begins.”

Previous research often focused only on either genetic mutations or cell type. Pollyea’s team looked at both, giving them a clearer understanding of how these two factors work together to influence treatment response.

“We learned that some cancer cells basically find a back door to evade the treatment,” said Pollyea. “By identifying how and why that happens, we can begin designing therapies that shut down those escape routes.”

For doctors, this research offers a powerful new way to classify AML patients by risk, meaning they can better predict who is likely to respond to venetoclax and who might need another approach.

“This is a major step toward personalized medicine in AML,” said Pollyea. “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.”

Pollyea and his team are working to expand the study with even more patient data and hope to design a clinical trial that uses this model to guide treatment decisions.

Other institutions that contributed to the study include the Knight Cancer Institute at Oregon Health and Science University; Hôpital Lyon Sud in Pierre-Bénite, France; CHU Clermont-Ferrand, France; Saint Priesten in Jarez, France; and the Lineberger Comprehensive Cancer Center at the University of North Carolina.