Patients undergoing treatment for lymphoma can sometimes develop a dangerous complication called therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (AML). Now a team of City of Hope researchers has discovered genetic markers that help identify which patients might be at risk.

The findings, which bring physicians closer to understanding the origins of these diseases, were published in the Nov. 15 edition of Cancer Cell.

Liang Li, right, and Sierra Min Li were lead authors on the Cancer Cell study. (Photo by p.cunningham)

Knowledge about how molecular mechanisms contribute to susceptibility to and emergence of t-MDS and AML could lead to ways to prevent or better treat these diseases, said Ravi Bhatia, M.D., director of the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope and co-principal investigator of the study.

Lead authors Liang Li, Ph.D., staff scientist in the Division of Hematopoietic Stem Cell and Leukemia Research, Sierra Min Li, Ph.D., assistant professor in the Division of Biostatistics, and fellow City of Hope researchers followed 700 Hodgkin and non-Hodgkin lymphoma patients for several years. Scientists began the study after patients received chemotherapy for lymphoma but before they showed evidence of leukemia. Patients then underwent autologous hematopoietic stem cell transplantation (in which patients received reinfusions of their own harvested stem cells). The researchers monitored patients for several years afterward.

Researchers compared gene expression in 18 patients who developed t-MDS or AML to expression in 37 matched patients who did not develop secondary blood disease. (The results later were validated in another set of patients, as well.)

In the case of lymphoma patients who eventually developed t-MDS/AML, researchers made a startling discovery: patients’ blood stem cells already showed early evidence of leukemia before their transplants.

“Changes associated with leukemia can actually be seen many years before the development of leukemia,” said Bhatia. “Patients and their cells and bone marrow may appear to be normal, but if you look at the deep molecular level, you can find that those changes are already there.”

Bhatia believes that specific genetic changes in stem cells put patients at risk for developing leukemia and that their treatment may have changed the stem cells even further, contributing to leukemia’s development. But some of these patients might have developed leukemia even without cancer treatment, he said.

Scientists next hope to validate the findings in a larger group of patients.

“In the future, we’ll want to evaluate whether the gene signature identifies patients at risk for leukemia even in the absence of transplant,” Bhatia said.

He also wants to explore whether patients who develop t-MDS/AML have greater risk of oxidative damage to their stem cells, and if so, whether targeting this abnormality might reduce risk of leukemia.

“The study has potential clinical significance, since early detection of patients at high risk for t-MDS/AML using a gene expression signature could facilitate interventions to prevent development of this lethal malignancy,” said Smita Bhatia, M.D., M.P.H., the Ruth Ziegler Chair in Population Sciences at City of Hope and co-principal investigator on the study.

This work could have broad implications. Ultimately, said Smita Bhatia, “we may be able to apply this knowledge to healthy people who are at risk of developing cancer — especially older individuals — and modify their risk.”

The work was supported by the National Institutes of Health as well as the Tim Nesvig Lymphoma Fellowship and Research Fund.