Certain chemotherapy drugs can cure lymphoma, yet also cause some patients to develop myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the leading cause of nonrelapse death in lymphoma patients. Now City of Hope researchers have identified genetic mutations in these patients that may be associated with a higher risk for therapy-related leukemia (t-MDS/AML).
The scientists presented their findings in December 2009 during the American Society of Hematology annual meeting in New Orleans.
 Yan Ding, left, and Smita Bhatia (Photo by p.cunningham) |
Molecular epidemiologist Yan Ding, Ph.D., M.S., assistant research professor in the Department of Population Sciences’ Division of Outcomes Research and lead author of the study, looked at key groups of genes involved with 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 the body’s cells cope with chemotherapy.
“The findings from this study are significant,” said Smita Bhatia, M.D., M.P.H., director of the Center for Cancer Survivorship at City of Hope and the study’s senior author. “The study gives us a glimpse of the subpopulation that is at high risk for developing therapy-related leukemia — a disease that has a poor prognosis.”
Ding, Bhatia and colleagues compared 46 patients with lymphoma who subsequently developed therapy-related leukemia to another 46 similar lymphoma patients who did not. “We looked at DNA polymorphisms and RNA expression, and tried 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.”
Researchers know that giving high doses of certain chemotherapeutic agents — topoisomerase II inhibitors and alkylating agents — can cause therapy-related leukemia in up to 10 percent of patients, especially those with lymphoma treated with autologous stem cell transplantation.
Many cancer treatments work by damaging cancer cells’ DNA and killing them through apoptosis, explained Ding. However, 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.
“We found that genes responsible for metabolizing these chemotherapeutic 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. Less efficient programmed cell death response to severe DNA damage may lead to accumulation of cells with chromosomal aberrations and put a patient 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, so physicians may better gear interventions toward them.
“Once we have confirmed these findings in a larger group of patients, we can examine the question of individualized therapy,” said Bhatia.
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.
