PHILADELPHIA—The Bcl-2 inhibitor ABT-199 and the Bruton tyrosine kinase inhibitor ibrutinib can have a synergistic effect against mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), preclinical data suggest.
In one set of experiments with MCL and CLL samples, the drugs induced apoptosis at a much higher rate when used together than when used alone.
However, in other experiments with CLL samples, ABT-199 and ibrutinib did not consistently display synergistic cytoxicity.
The researchers said this indicates substantial patient heterogeneity in response to the combination that may be due to variations in the genetic landscape.
Michael J. Weber, PhD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues presented this research at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies.
“We took an empirical but systematic approach to identify combinations of drugs that might improve the ability of ibrutinib to kill cancer cells,” Dr Weber said. “The combination of ibrutinib and ABT-199 was, by far, the most effective in our assays, and we are in the very earliest stages of planning a clinical trial to test this combination in the clinic.”
In previous studies, Dr Weber and his colleagues found that ibrutinib synergized with both ABT-199 and the proteasome inhibitor carfilzomib to kill MCL cell lines. In this study, the team assessed the effects of exposure to these 2 combinations on samples from patients with MCL or CLL.
The researchers found that apoptosis occurred in 23% of cells exposed to ABT-199 and ibrutinib in combination, compared to 3.8% of cells exposed to ibrutinib and 3% exposed to ABT-199.
The combination of ibrutinib and carfilzomib also increased apoptosis in MCL and CLL cells compared to either agent alone, though to a lesser degree than the ABT-199 combination. Apoptosis occurred in 5.5% of cells exposed to ibrutinib and carfilzomib, 3.8% exposed to ibrutinib, and 1.7% exposed to carfilzomib.
The researchers observed minimal apoptosis in normal T cells, both with the single agents and the combinations.
Further analysis showed that ibrutinib and ABT-199 worked synergistically to cause apoptosis in leukemic cells from 5 of 9 patients with CLL.
According to Dr Weber, the variable response to this combination points to the importance of understanding how these combinations work, so we can match the treatments with the most appropriate patients.
“Ibrutinib and ABT-199 target different pathways involved in promoting cancer cell survival and growth,” Dr Weber said.
“This is very intriguing because, in most instances where cancer cells are resistant to a particular molecularly targeted drug, we find that cancer cells adapt and find new ways to reactivate the pathway being targeted by the drug and that combinations of drugs targeting this pathway in different ways can improve outcomes. Here, we found that targeting a pathway outside the primary pathway was effective.”
This study was funded by the University of Virginia Cancer Center. Dr Weber declared no conflicts of interest.
