It’s a cruel irony that some chemotherapy drugs can cure lymphoma, yet also cause some patients to then develop myelodysplastic syndrome or acute myeloid leukemia.

Understanding how this happens is vitally important because, other than relapse, therapy-related leukemia is the leading cause of death in lymphoma patients.

Yan Ding, left, and Smita Bhatia (Photo by p.cunningham)

Now City of Hope researchers have identified genetic mutations in some patients that may be linked to a higher risk for therapy-related leukemia.

Molecular epidemiologist Yan Ding, Ph.D., M.S., assistant research professor in the Department of Population Sciences’ Division of Outcomes Research at City of Hope, looked at key groups of genes involved in three areas of a cell’s inner workings: DNA repair, drug metabolism and apoptosis (a sort of programmed death most cells undergo when they are damaged). Differences in these genes affect how well cells cope with chemotherapy.

According to Smita Bhatia, M.D., M.P.H., chair of the Department of Population Sciences and director of the Center for Cancer Survivorship at City of Hope, the study gives us a glimpse of who is at high risk for developing therapy-related leukemia.

Ding, Bhatia and colleagues compared 46 patients with lymphoma who went on to develop therapy-related leukemia to another 46 similar lymphoma patients who did not.

The team looked at subtle differences in the patients’ DNA and how active their genes were. The scientists aimed “to understand the differences at the genetic level between the two groups,” Bhatia said. “We were able to get an idea of the genetics of why certain patients develop therapy-related leukemia.”

Many chemotherapy agents, as well as radiation therapy, work by damaging cancer cells’ DNA and killing them through apoptosis, explained Ding. Unfortunately, these treatments also can harm healthy cells. The body’s ability to help healthy cells resist and overcome damage is linked to its genetic makeup.

The researchers found that genes responsible for metabolizing the chemotherapy agents were different in the patients who developed therapy-related leukemia versus those who did not, Bhatia said.

In addition to genes that control drug metabolism, they also found differences between the groups in certain genes that repair damaged DNA.

“When a chemotherapeutic agent damages the DNA, most individuals have the ability to repair it immediately — but some don’t,” said Bhatia. “The damaged DNA then can lead to leukemia.”

The team found similar patterns of genetic mutations related to apoptosis. If a patient’s genetic makeup makes them less efficient at killing off cells with severely damaged DNA, they might accumulate cells with marred genes and chromosomes. This can put them at risk for leukemia.

Bhatia noted that the findings of this study, when confirmed in larger populations, could help researchers understand and predict who might be at risk for developing therapy-related leukemia. And that could help physicians gear their treatments appropriately.

Ultimately, researchers hope that genetic tests done before treatment may eventually point physicians and their patients away from therapies likely to cause leukemia after treatment.