A combined regimen of inhibitors targeting B-cell lymphoma 2 (BCL-2) and BCR-ABL tyrosine kinase completely eradicated chronic myeloid leukemia (CML) in mice, raising the possibility of a cure for humans, according to the authors of a recent study.1
“We did serial transplantation in a mouse model that’s considered the best model for this disease and we reduced the ability or abolished the ability to cause leukemia in the system,” said Michael Andreeff, MD, professor in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston. “That opens the possibility that we could convert patients who have partial responses, or what we call molecular responses, but not complete molecular responses, into real cures.”
Dr Andreeff led the study along with his department colleague Bing Carter, PhD; the findings were published in Science Translational Medicine.
The standard of care treatment with BCR-ABL inhibitors allows most patients with CML to remain in remission, but does not completely eliminate the disease. “BCR-ABL tyrosine kinase inhibitors (TKIs) are effective against CML, but they rarely eliminate CML stem cells,” the authors wrote. “Disease relapse is common upon therapy cessation, even in patients with complete molecular responses. Furthermore, once CML progresses to blast crisis (BC), treatment outcomes are dismal.”
Approximately 100,000 patients in the US are kept on life-long TKI therapy with drugs such as imatinib (Gleevec), Dr Andreeff noted, at a cost of about $100,000 annually.
“The prognosis was survival of 3-1/2 to 4-1/2 years. And then came Gleevec, which changed the world. Survival now is in the, perhaps, 80% range, but the price is extraordinary,” he said. “The idea is to get patients off this drug and have them totally cured, not just to suppress the disease.”
The authors note that cost is only 1 consideration. “Acquired BCR-ABL mutations that render TKIs ineffective can develop, and in patients progressing to BC, there are no meaningful responses to TKIs and survival is counted in weeks or months.”
In a press release accompanying the announcement of the study’s results, Dr Carter explained that, “It is believed that TKIs do not eliminate residual stem cells because they are not dependent on BCR-ABL signaling. Hence, cures of CML with TKIs are rare.”2
Using mice as the model, the researchers focused their study on eliminating the leukemia stem cells with a 2-pronged assault on the cancer-causing agents.