Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia

Abstract

Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKIs) have revolutionized how CML is treated. While the majority of patients respond to these kinase inhibitors, a subset become resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently FDA approved for Philadelphia-positive CML either in chronic or accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in chronic phase and major hematologic response in 27% of patients in accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life which makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins such as Bcr-Abl followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.

Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

“…1) for the treatment of chronic myelogenous leukemia (CML). 5 Molecules that suppress protein synthesis are also valuable biochemical tools; for example, cycloheximide (CHX; 2 ) has played an important role in experiments to determine protein half-lives, 6 among many other applications. 7,8 …”

Chronic myeloid leukemia: reminiscences and dreams

“…It has actually been under investigation in CML and other myeloid malignancies since the 1970s. 138 The results of recent studies were encouraging, with modest activity noted in patients with CML in the chronic and advanced phases, including some with the T315I subclone. The drug was licensed in 2014 for use in patients with CML (all phases) who were resistant or intolerant to two or more TKIs.…”

Is there a role for omacetaxine in the management of chronic myelogenous leukemia in the era of the tyrosine kinase inhibitors?

“…This distinct property of omacetaxine makes it less susceptible to tyrosine kinase mutations which confer resistance to TKI therapy, such as the gatekeep ing mutation T315I. Clinical activity was demonstrated in patients with CML and was the basis for accelerated approval by the US Food and Drug Administration in October 2012 for patients with CP and AP CML failing two prior TKI agents [5]. The drug is administered as a subcutaneous injection twice daily with induction followed by a maintenance schedule.…”