A research team at Oregon Health & Science University has identified a promising drug combination that could significantly improve outcomes for patients with acute myeloid leukemia (AML). By pairing the standard AML treatment venetoclax with palbociclib, a drug initially approved for breast cancer, researchers observed enhanced anti-leukemia activity, overcoming some of the resistance seen with existing therapies. Their findings were published in the journal Cell Reports Medicine on March 15, 2024.
The study analyzed over 300 patient samples and confirmed that the combination of venetoclax and palbociclib produced stronger and more durable effects compared to venetoclax alone. This conclusion was supported by tests on human tissue samples and mouse models that carried human leukemia cells. The researchers noted that this combination effectively targets both cell cycle and protein synthesis pathways, addressing mechanisms of resistance commonly associated with either drug when used independently.
According to Melissa Stewart, PhD, the lead author of the study, “Of the 25 drug combinations tested, venetoclax plus palbociclib was the most effective. That really motivated us to dig deeper into why it works so well.” This exploration is vital as resistance to current AML treatments remains a widespread issue.
Every year, more than 20,000 people in the United States receive an AML diagnosis, making it one of the most aggressive types of leukemia. Since the FDA approved venetoclax in 2019, it has become a primary treatment option when combined with the hypomethylating agent azacitidine. Despite this, the five-year survival rate for AML patients hovers between 25% and 40%, underscoring the need for improved therapies.
In the study, the team employed ex vivo drug sensitivity assays to evaluate 302 AML samples, identifying venetoclax and palbociclib as one of the most effective combinations. Palbociclib, known for its role in treating hormone receptor-positive advanced breast cancer, had not been extensively studied in the context of hematological malignancies until now.
The research revealed that AML cells often increase protein production when exposed to venetoclax alone, which can help them survive treatment. The addition of palbociclib counteracts this adaptation, regulating the cell’s protein synthesis machinery. “Patient samples that responded strongly to the combination showed clear downregulation of genes involved in protein synthesis,” Stewart explained.
A genome-wide CRISPR screen conducted as part of the study indicated that while venetoclax alone becomes more effective when protein-production genes are lost, the combination treatment does not rely on these vulnerabilities. “Our CRISPR screen showed that RB1 and other cell cycle genes conferred resistance to palbociclib,” the researchers noted. Interestingly, the combination therapy remained effective regardless of the loss of specific genes, suggesting that it mitigates several clinically relevant resistance mechanisms.
The research included tests on mouse models implanted with human AML cells that were known to exhibit resistance to venetoclax. In these models, venetoclax alone did not extend survival, but the combination therapy resulted in a significant improvement, with most mice living for 11 to 12 months. One mouse remained alive at the end of the study, highlighting the treatment’s potential.
While the combination appears promising, the study identified a subpopulation of patients with mutations in IKZF1—occurring in about 3-5% of AML cases—who are unlikely to benefit from this regimen. These patients often display poor treatment responses due to the upregulation of the AXL receptor, which can lead to resistance against targeted therapies. The team suggested that AXL inhibitors could provide an effective strategy for this challenging patient group.
In summary, the research establishes venetoclax plus palbociclib as a potentially effective treatment regimen for AML, especially for patients lacking IKZF1 mutations or those with acquired RB1 or BAX mutations. Jeffrey Tyner, PhD, a co-leader of the national Beat AML 1.0 program, emphasized the importance of this work in expanding treatment options.
“This combination was nominated from the Beat AML data, and Dr. Stewart validated that prediction, showing not only that it works, but why,” Tyner stated.
Stewart, who is a breast cancer survivor herself, expressed personal motivation behind the research. “I know what it’s like to be a cancer patient. The hope that research and clinical trials can bring—that’s what motivates me,” she said.
The researchers are now looking to evaluate other drugs similar to palbociclib that are also approved for breast cancer, aiming to broaden future clinical trial options. Tyner highlighted the importance of pursuing scientific data, even when it leads outside traditional boundaries. “Biology can be shared across very different cancers. This is a great example of why keeping an open mind is crucial.”
Moving forward, the research team intends to advance their findings toward clinical testing, believing that their combination treatment could effectively address many of the known resistance mechanisms associated with current AML therapies.
