Combining the Telomerase Inhibitor Imetelstat with the BCL-2 Inhibitor Venetoclax Enhances Apoptosis and Improves Survival in Acute Myeloid Leukemia Cellular and Animal Models.

Background/

Objectives

Acute myeloid leukemia (AML) is a heterogeneous disease with limited treatment options. New therapies with novel mechanisms of action are needed. Telomerase and BCL-2 are overexpressed in AML and correlate with disease severity and poor prognosis, suggesting dual targeting may be beneficial.

Methods

We evaluated the effect of imetelstat, a telomerase inhibitor, in combination with venetoclax, a BCL-2 inhibitor, in AML cell lines, AML patient-derived samples, and in a MOLM-13 AML xenograft model.

Results

In AML cell lines and patient samples, imetelstat plus venetoclax demonstrated dose-dependent synergistic activity to induce apoptosis. Studying AML patient samples ex vivo showed the effect is preferentially in CD34+ leukemic cells, and not in lymphocytes. The synergy induced by venetoclax plus imetelstat was stronger than venetoclax plus hypomethylating agents in AML cell lines. The in vivo MOLM-13 AML xenograft model demonstrated that imetelstat plus venetoclax prolonged survival of tumor-bearing mice compared to either agent alone. Forty percent of mice in the combination group were still alive eighty days after the end of treatment, whereas all mice in the single-agent groups succumbed to disease within two weeks. Mechanisms of synergy elicited by the combination were further illustrated through reduction of hTERT expression and telomerase activity, decreases in the interaction of BCL-2 with BAX, and enhanced mitochondrial dysfunction via loss of mitochondrial membrane potential, and these led to marked increases in the intrinsic mitochondrial apoptosis pathway in AML cells.

Conclusions

This study supports the clinical evaluation of imetelstat plus venetoclax for the treatment of AML in the Phase 1 IMAGINE trial (NCT07320235).