Acute myeloid leukemia, or AML, is a fast-growing cancer of the blood and bone marrow.
Although treatment has improved in recent years, the disease remains difficult to cure because some cancer cells can survive therapy and later cause the leukemia to return.
Researchers at Thomas Jefferson University have now found a promising way to attack these hard-to-kill cells.
In laboratory studies and mice, a combination of three drugs killed far more leukemia cells than the researchers saw with individual drugs or two-drug treatments.
The research was published in Science Advances. The team was led by cancer biologist Dr. Sara Meyer, with graduate student Melanie Goetz as the study’s first author.
AML begins when immature blood-forming cells in the bone marrow grow out of control. These abnormal cells crowd out healthy cells that normally become red blood cells, infection-fighting white blood cells and platelets.
Because AML can progress quickly, treatment often needs to begin soon after diagnosis. Chemotherapy has long been a major treatment, while newer targeted medicines can attack particular weaknesses in leukemia cells.
However, even when treatment removes most of the cancer, a small group of leukemia stem cells may remain. These cells can survive treatment, rebuild the cancer and contribute to relapse.
The researchers focused on a drug called inobrodib, which is being studied as a possible cancer treatment. Early clinical research has suggested that it has activity against some blood cancers, but scientists have suspected that it may work better when combined with other medicines.
The Jefferson team first tested inobrodib in models of AML. The drug slowed the growth of leukemia and helped mice survive longer, showing that it was having a meaningful effect on the disease.
But there was an important weakness. Inobrodib alone did not successfully remove the leukemia stem cells that can keep the cancer alive after treatment.
That led the researchers to search for drugs that could strengthen its effects. They combined inobrodib with venetoclax and gilteritinib, two medicines already approved by the U.S. Food and Drug Administration for use in certain patients with AML.
Venetoclax works by blocking a protein that cancer cells can use to avoid death. Gilteritinib targets an abnormal signal found in some AML cells, particularly those carrying changes in a gene called FLT3.
When all three medicines were used together, the results were much stronger than with the other treatments tested. The triple combination caused more leukemia cell death than any individual drug or any two-drug combination.
The difference was particularly clear in leukemia stem cells. Mice given all three drugs had about 10 times fewer leukemia stem cells remaining in their bone marrow than mice receiving the next most effective treatment.
The researchers also tested the combination on AML samples taken from patients. Again, the three medicines caused extensive cancer cell death, providing additional evidence that the approach may be worth investigating in people.
This is important because relapse remains one of the biggest challenges in AML treatment. A therapy that kills the main leukemia population but leaves cancer stem cells behind may produce a temporary improvement without preventing the disease from returning.
By attacking those surviving cells more effectively, the new combination could potentially produce deeper and longer-lasting responses. The researchers are now working with clinicians, collaborators and the company developing inobrodib to explore a clinical trial in people with AML that has returned or resisted treatment.
Still, the findings are preclinical and should not be interpreted as proof that the combination will work safely in patients. Results in mice and laboratory samples can be encouraging, but human trials are needed to determine the correct doses, side effects and actual effects on survival.
The use of three powerful cancer drugs together could also create safety challenges. Researchers will need to determine whether patients can tolerate the combination and whether its ability to destroy leukemia cells outweighs any additional side effects.
Overall, the study provides a strong reason to investigate the three-drug strategy further. Its most encouraging feature is not simply that it killed large numbers of AML cells, but that it sharply reduced the stem-like cells believed to play a central role in treatment resistance and relapse.
For patients with relapsed or resistant AML, new options are urgently needed. If future clinical trials confirm these results, targeting leukemia from several directions at once could become a valuable way to make treatment more durable.
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