Shedding Light on Tumor Dynamics: Focus on Ibrutinib and Venetoclax in CLL
Posted: Wednesday, May 12, 2021
A study performed by Y. Lynn Wang, MD, PhD, of the Fox Chase Cancer Center, Philadelphia, and colleagues used an ex vivo model to investigate how chronic lymphocytic leukemia (CLL) cells respond to venetoclax, ibrutinib, and a combination of the two. Their work, which was published in Blood Cancer Journal, demonstrated that both drugs act on specific cell subpopulations, providing a basis for clinical observations associated with these drugs.
“The data imply that the inability of each of the drugs to act on the entire CLL population may account for the persistence of residual disease,” the researchers concluded. “These data collectively provide a strong laboratory rationale that combining these two drugs may have the potential for a cure, consistent with the current clinical observations.”
Peripheral blood samples were collected from 31 patients with CLL. CLL cells were then isolated and assessed for purity and viability. Long-term cultures of bone marrow cells from a 73-year-old patient with CLL were used to create the bone marrow fibroblast cell line. Along with a bone marrow fibroblast monolayer, carboxyfluorescein succinimidyl ester (CFSE)-labeled cells were placed in 24 well plates; CpG and interleukin-15 were added to all except control cells. Ibrutinib or venetoclax were added to co-cultures, and an equal volume of dimethylsulfoxide was added to control wells.
In ibrutinib-resistant patients treated with ibrutinib, cell viability and proliferation were reduced from 100% to 77% and 87% to 68%, respectively. However, ibrutinib did not cause any significant changes to cell viability. Ibrutinib also significantly reduced the percentage of proliferating CLL cells in sensitive cases. In contrast, venetoclax increased the amount of proliferating cells and reduced the number of live cells, regardless of ibrutinib sensitivity. Although venetoclax and ibrutinib target distinct CLL cell populations with contrasting proliferative capacities, their combined use demonstrated the most effective cell killing (P = .001).
Disclosure: For full disclosures of the study authors, visit nature.com.
