Wake Forest leukemia research suggests personalized approach to chemo

Leukemia research at Wake Forest Baptist Medical Center has found a mutation in a protein that could open doors to a personalized medicine approach to treating the disease by limiting use in certain patients of a particularly toxic drug.

The researchers at Wake Forest Baptist in Winston-Salem, North Carolina, found that a particular mutation of the FLT3 receptor alters a patient’s response to standard therapy. They were studying acute myeloid leukemia, an aggressive form of cancer that primarily affects the elderly and the most common form of acute leukemia in adults.

Researchers studied mice that had leukemia to examine their responsiveness to cytarabine and doxorubicin, two drugs used in combination as a standard chemotherapy treatment for AML patients. They found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin. But the cells are also made extra sensitive to cytarabine when the drugs are administered separately. Researchers also found that the mutation causes the cells to be resistant overall to the combination of the drugs.

Doxorubicin is in a class of extremely toxic drugs known as anthracyclines. While these drugs target cancer cells, they can also suppress normal cells in the bone marrow and cause cardiac toxicity, which can injure the heart muscle and sometimes cause heart failure.

Dr. Timothy Pardee, an assistant professor of hematology and oncology, said in a prepared statement that mice who had the mutation seemed to be able to repair the DNA damage caused by doxorubicin. Mice treated with doxorubicin died at the same rate as those that received no treatment at all. While the mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

“It’s almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell,” Pardee said. “When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it.”

Pardee said that more studies will be needed to determine how applicable the findings are in humans. But the animal model suggests that those who have the mutation get no benefit from receiving the second, toxic drug doxorubicin.

“We’re hopeful that in the future, these findings will lead to more personalized patient care,” Pardee said. “The ‘one-size-fits-all’ approach to treating AML needs to be re-examined.”

Results of the study have been published in Experimental Hematology. Pardee is the lead author of the study. Financial support for the research included funding from the Leukemia and Lymphoma Society, National Cancer Institute and the Wake Forest University Comprehensive Cancer Center.