Michael J. Weber, PhD
The combination of ABT-199 and ibrutinib (Imbruvica) demonstrated promising early activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) cell lines, according to data presented at a special AACR conference focused on hematologic malignancies.1
In the analysis, synergistic apoptosis was observed with the combination of ABT-199 and ibrutinib in circulating tumor cells (CTCs) from patients with CLL and MCL. Molecular analysis in the study suggested that interactions between p53 and BIM were responsible for the synergy between the two agents. Moreover, off-target apoptosis was not seen in normal T-cells.
“We took an empirical but systematic approach to identify combinations of drugs that might improve the ability of ibrutinib to kill cancer cells,” Michael J. Weber, PhD, professor of microbiology, immunology, and cancer biology at the University of Virginia School of Medicine in Charlottesville, said in a statement. “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 the study, CTCs collected from peripheral blood buffy coat samples from patients with CLL and MCL were exposed to various treatments at pharmacologically achievable doses for 72 hours. Single-agent ibrutinib, ABT-199, and carfilzomib were administered along with combinations of ibrutinib plus ABT-199 and ibrutinib plus carfilzomib.
Apoptosis in B-cells was measured through analysis of CD3-, CD5-, and CD19+ cells. Additionally, T-cell apoptosis was analyzed through CD3+, CD5+, and CD19- cells.
The combination of ibrutinib and ABT-199 induced cellular apoptosis in 23% of samples compared with 3.8% for single-agent ibrutinib and 3.0% with ABT-199. Apoptosis was induced in 5.5% of samples with the combination of ibrutinib and carfilzomib compared with 3.8% with ibrutinib and 1.7% with carfilzomib.
Minimal apoptosis was seen in T-cell samples. Additionally, in samples from healthy donors, no increased apoptosis was noted.
Ibrutinib is an irreversible BTK inhibitor that works by blocking B-cell activation and signaling, preventing the growth of malignant B cells that overexpress BTK. ABT-199 is a bioavailable selective inhibitor of the Bcl-2 protein, which is critical to the pathogenesis of many hematologic malignancies. Moreover, preclinical evidence suggests that Bcl-2 overexpression is a main mediator of resistance to chemotherapy.
Gene expression profiling revealed transcriptional changes following the administration of ibrutinib. The combination of ibrutinib and ABT-199 showed both transcriptional potentiation changes and emergent transcriptional changes. The two proteins potentially responsible for apoptosis with the combination were identified as p53 and BIM.
“Ibrutinib and ABT-199 target different pathways involved in promoting cancer cell survival and growth,” 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 builds on earlier work published in Leukemia
, exploring ibrutinib in combination with 14 other agents being investigated as treatments for B-cell maligancies.2
The most promising combinations identified in the study were those targeting non-BCR pathway targets, specifically ABT-199 and carfilzomib.
A phase I/IIb clinical trial exploring ibrutinib in combination with carfilzomib is currently enrolling for patients with relapsed/refractory MCL. The phase I portion will establish a dose for the two agents, while the phase IIb segment will evaluate progression-free survival. The study hopes to enroll 223 patients (NCT01962792).
“Ibrutinib was recently approved by the FDA for the treatment of both mantle cell lymphoma and chronic lymphocytic leukemia,” Weber explained.
The FDA initially approved ibrutinib for patients with MCL who received at least one prior therapy in November 2013. The drug was approved as a treatment for patients with previously treated CLL in February 2014, which was followed by a full FDA approval in July. This was based a significant improvement in progression-free survival and overall survival for patients with CLL in the phase III RESONATE trial.
“Unfortunately, about one-third of patients have disease that is resistant to ibrutinib, and even for those who have disease that responds, in very few cases is it a complete response. This problem of treatment resistance is one of the biggest challenges in cancer treatment at the moment,” Weber said.
Portell CA, MJ Axelrod, Brett LK, et al. Synergistic Cytotoxicity of Ibrutinib and the BCL2 Antagonist ABT-199 in Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia: Molecular Analysis Reveals Mechanisms of Target Interactions. Presented at: AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA.
Axelrod M, Ou Z, Brett, LK, et al. Combinatorial drug screening identifies synergistic co-targeting of Bruton’s tyrosine kinase and the proteasome in mantle cell lymphoma. Leukemia. Published online October 8, 2013.