At first, the drug imatinib (brand name Gleevec) seemed a miracle treatment for patients diagnosed with chronic myelogenous leukemia, or CML. It’s taken by mouth and seems 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. City of Hope researchers now know why.
Ravi Bhatia studies stem cells that cause leukemia. (Photo by Walter Urie)
The culprit appears to be cancer-causing stem cells that can linger in the bone marrow even after years of effective cancer control with imatinib.
A study led by Division of Hematopoietic Stem Cell and Leukemia Research investigators Su Chu, M.D., staff scientist, and Ravi Bhatia, M.D., professor and director of the division, appeared to confirm long-held suspicions about the root cause of CML relapse in these patients.
CML is driven by an abnormal gene called BCR-ABL. Imatinib works by binding to the protein that BCR-ABL produces. That neutralizes the cancerous cells and causes them to kill themselves.
In early studies, imatinib seemed to destroy all CML cells that produce the BCR-ABL protein.
But the City of Hope group wasn’t so sure the drug wiped out all the cells. In their first studies they looked for molecular clues that CML was still there — and they found them, even though patients had no signs of leukemia. When they took a deeper look, they found that these patients had faulty stem cells that would lead to CML, even when patients took the drug for as long as two years.
In some studies, though, the drug appeared to completely eliminate the leukemia in patients if taken for long enough. That left the City of Hope scientists wanting to know more.
In their latest study, they analyzed bone marrow samples from CML patients who had taken imatinib for four or more years. They found that patients who had shown no signs of CML for a long time still had stem cells with active BCR-ABL genes, and BCR-ABL activity did not further decrease over time.
And when they studied the patients’ CML stem cells in the lab, they found the cells could regenerate leukemia in laboratory models, showing that relapse remained possible despite prolonged leukemia treatment.
Bhatia sees the results as evidence that imatinib may never completely do away with CML in most patients.
But that’s not the end of the story: His team is studying drugs that target residual leukemia stem cells, work that’s led to an open clinical trial of one such drug.
“These results provide further evidence that new therapies are needed if we want to eventually eliminate disease and cure patients of their CML,” Bhatia said.