Preclinical research suggests that combining a BCL2 inhibitor with a BCR-ABL tyrosine kinase inhibitor (TKI) can eradicate leukemia stem cells (LSCs) in chronic myeloid leukemia (CML).
In mouse models of CML, combining the TKI nilotinib with the BCL2 inhibitor venetoclax enhanced antileukemic activity and decreased numbers of long-term LSCs.
The 2-drug combination exhibited similar activity in samples from patients with blast crisis CML.
“Our results demonstrate that . . . employing combined blockade of BCL-2 and BCR-ABL has the potential for curing CML and significantly improving outcomes for patients with blast crisis, and, as such, warrants clinical testing,” said Michael Andreeff, MD, of the University of Texas MD Anderson Cancer Center in Houston.
Dr Andreeff and his colleagues reported these results in Science Translational Medicine. The study was funded by National Institutes of Health, the Paul and Mary Haas Chair in Genetics, and Abbvie Inc., the company developing venetoclax.
The researchers noted that, although BCR-ABL TKIs have proven effective against CML, they rarely eliminate CML stem cells.
“It is believed that TKIs do not eliminate residual stem cells because they are not dependent on BCR-ABL signaling,” said study author Bing Carter, PhD, also of MD Anderson Cancer Center. “Hence, cures of CML with TKIs are rare.”
Dr Carter has worked for several years on eliminating residual CML stem cells, which could mean CML patients would no longer require long-term treatment with TKIs. Based on the current study, she and her colleagues believe that combining a TKI with a BCL-2 inhibitor may be a solution.
The researchers found that targeting both BCL-2 and BCR-ABL with venetoclax and nilotinib, respectively, exerted “potent antileukemic activity” and prolonged survival in BCR-ABL transgenic mice.
After stopping treatment, the median survival was 34.5 days for control mice, 70 days for mice treated with nilotinib alone (P=0.2146), 115 days for mice treated with venetoclax alone (P=0.0079), and 168 days for mice treated with nilotinib and venetoclax in combination (P=0.0002).
Subsequent experiments in mice showed that nilotinib alone did not significantly affect the frequency of long-term LSCs, although venetoclax alone did. Treatment with both drugs reduced the frequency of long-term LSCs even more than venetoclax alone.
Finally, the researchers tested venetoclax, nilotinib, and the combination in cells from 6 patients with blast crisis CML, all of whom had failed treatment with at least 1 TKI.
The team found that venetoclax and nilotinib had a synergistic apoptotic effect on bulk and stem/progenitor CML cells.
The researchers said these results suggest that combined inhibition of BCL-2 and BCR-ABL tyrosine kinase has the potential to significantly improve the depth of response and cure rates of chronic phase and blast crisis CML.
“This combination strategy may also apply to other malignancies that depend on kinase signaling for progression and maintenance,” Dr Andreeff added.
