At first, Gleevec seemed a miracle treatment for patients diagnosed with chronic myelogenous leukemia, or CML. The oral medication appeared to vanquish the disease with unexpected ease. Despite years of taking the drug, however, CML patients still face the threat of relapse if they stop their treatment, and City of Hope researchers now know why.
Su Chu (Photo by Darrin S. Joy)
Division of Hematopoietic Stem Cell and Leukemia Research scientists led a study that found CML-causing stem cells linger in the bone marrow after years of effective cancer control with Gleevec, also called imatinib. Su Chu, M.D., staff scientist, and Ravi Bhatia, M.D., director of the division, spearheaded the research, which appeared online on Sept. 19 in Blood.
The study confirmed scientists’ long-held suspicions about the root cause of CML relapse in these patients.
CML is driven by an abnormal gene called BCR-ABL. Imatinib targets the protein that BCR-ABL produces, neutralizing the malignant cells that generate it and causing them to undergo cell suicide.
Previous research in Bhatia’s lab has found molecular evidence that CML persists in patients who receive imatinib even when the patients show no clinical signs of disease. Looking deeper, the scientists also found CML-forming stem cells that had active BCR-ABL genes as long as two years after beginning imatinib treatment.
“On the other hand, researchers have seen a slow but steady decline in BCR-ABL levels with prolonged imatinib treatment and in some cases treatment has been stopped without disease relapse,” Chu said. Those results suggest that CML potentially could be completely eradicated if patients receive the drug for long enough.
Hoping to find a clear answer, the researchers undertook the current study. They collected bone marrow samples from CML patients after four or more years of imatinib treatment and found that patients in prolonged remission still had stem cells that expressed BCR-ABL. In addition, BCR-ABL expression did not further decrease over time.
The remaining leukemia stem cells also were capable of regenerating leukemia cells after transplantation into mice, showing that CML relapse remained possible despite prolonged leukemia treatment.
Bhatia sees the results as evidence that imatinib may never completely do away with CML-forming blood stem cells in most patients. His team has done extensive research with drugs that target residual leukemia stem cells, and their work has led to a clinical trial of one such drug, currently under way.
“These results provide further evidence that new therapies are needed if we want to eventually eliminate disease and cure patients of their CML,” he said.
Other authors on the study include Tinisha McDonald, Allen Lin, Sujata Chakraborty, Ph.D., Qin Huang, M.D., Ph.D., and David Snyder, M.D.
Funding for the study came from the National Institutes of Health and the Leukemia & Lymphoma Society.