For many people with acute myeloid leukemia, the greatest danger is not only the cancer that doctors can see at diagnosis.
The bigger long-term problem may be a small population of unusually tough leukemia cells that survives treatment and allows the disease to grow back.
A new study from Thomas Jefferson University suggests that attacking AML with three medicines at the same time may greatly reduce this hidden source of relapse.
The experimental treatment left far fewer leukemia stem cells behind than other drug approaches tested by the researchers.
The findings were published in the journal Science Advances. Senior author Dr. Sara Meyer and her team investigated whether an experimental drug called inobrodib could become more powerful when paired with existing leukemia medicines.
AML is an aggressive cancer that develops in the bone marrow, the soft tissue inside bones where blood cells are produced. In the disease, abnormal immature cells multiply rapidly and interfere with the body’s ability to make healthy blood cells.
This can lead to tiredness and weakness from too few red blood cells, infections from a shortage of healthy white blood cells, and bleeding or bruising when platelet numbers fall. The disease can worsen rapidly without treatment.
Modern AML care is becoming increasingly personalized. Doctors can test leukemia cells for genetic changes and other features, then use medicines designed to target some of the weaknesses created by those changes.
Even so, AML frequently returns after an initial response. One reason is that not every cancer cell behaves in the same way.
Some cells have stem-like properties and can survive conditions that kill many other leukemia cells. If only a small number remain after treatment, they may eventually produce a new population of cancer cells and cause relapse.
The Jefferson researchers wanted to find a treatment that could reach this stubborn population. They began with inobrodib, an experimental drug that has already shown promise in early clinical studies but may not be strong enough to produce lasting results when used alone.
In mice with AML, inobrodib slowed the leukemia and extended survival. Yet closer examination showed that leukemia stem cells were still present, meaning the disease retained a possible route to return.
The researchers therefore combined inobrodib with two established targeted medicines: venetoclax and gilteritinib. Both are FDA-approved drugs used in AML treatment, although their use depends on a patient’s disease and other clinical factors.
Venetoclax makes it harder for certain cancer cells to protect themselves from programmed cell death. Gilteritinib blocks FLT3, a growth signal that can become abnormally active in some forms of AML.
Bringing the three medicines together produced the strongest effect in the study. The triple treatment killed more cancer cells than any of the single medicines and more than any pair of drugs the team tested.
The impact on leukemia stem cells was especially notable. After treatment, mice receiving the three-drug regimen had roughly one-tenth as many leukemia stem cells in their bone marrow as mice receiving the next best treatment.
The scientists then studied AML cells obtained from patients. The same three-drug approach caused widespread death of cancer cells in these samples, suggesting that the effect was not limited to the mouse experiments.
The result points toward an important idea in cancer treatment: sometimes the most effective strategy is not simply to use a stronger drug, but to block several survival routes at the same time. If one medicine leaves a weakness in the treatment, another drug may be able to close that escape route.
For AML, that could be particularly valuable because resistant disease can be extremely difficult to treat. Patients whose leukemia returns after therapy often have fewer treatment choices and may face a poor outlook.
The researchers are now discussing how the approach could move toward a clinical trial for people with relapsed or treatment-resistant AML. Such a trial would be necessary before doctors could know whether the dramatic laboratory results translate into meaningful benefits for patients.
There are several unanswered questions. A three-drug treatment may increase side effects, and scientists will need to establish safe doses, identify which patients are most likely to benefit and determine whether reducing leukemia stem cells actually prevents relapse for longer periods.
The study also cannot show from preclinical experiments alone that the treatment improves human survival. Patient samples can reveal whether cancer cells respond to drugs in the laboratory, but the human body is far more complicated.
Even with these limitations, the findings are encouraging because the researchers targeted one of AML’s most difficult features rather than measuring only short-term cancer cell killing. The roughly tenfold reduction in leukemia stem cells provides a strong reason to continue testing the approach.
If human trials eventually show similar results with acceptable side effects, the strategy could offer a new option for people whose AML has resisted other treatments. For now, it represents a promising step toward stopping the small population of cells that can allow this aggressive cancer to return.
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Source: Thomas Jefferson University.
