Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

SIMPLE SUMMARY: About 20% of children with acute myeloid leukemia (AML) experience refractory disease or relapse, despite receiving intensive therapy. Leukemia stem cells (LSC) have the ability to evade chemotherapy and propagate the disease leading to chemoresistance and relapse. Therefore, treatment options that are able to eliminate LSCs are likely to be more effective in prolonging disease-free survival. We have tested the effect of imetelstat, a potent inhibitor of telomerase activity that specifically kills LSCs, on pediatric AML cells in culture and in mouse models. Imetelstat was effective in specifically killing LSCs and extended animal survival when used as a single agent or in combination with chemotherapy or epigenetic drug azacitidine. ABSTRACT: Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.