OMACETAXINE: A PROTEIN TRANSLATION INHIBITOR FOR THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA (CML)

Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by the BCR-ABL fusion oncogene with constitutive tyrosine kinase activity and uncontrolled cell proliferation. Although tyrosine kinase inhibitors (TKIs) are the current standard of therapy, resistance to therapy-most notably the BCR- ABL kinase domain mutations T3151—is a significant challenge. Omacetaxine mepesuccinate,a novel first- in-class reversible protein translation inhibitor, has been proven to be an valuable therapeutic choice for TKI- resistant CML. By occupying the ribosomal A-site, omacetaxine blocks elongation of protein synthesis, resulting in degradation of short-lived oncoproteins such as BCR-ABL and Mcl-1, which supports apoptosis. Its effectiveness has been shown in patients with multi-TKI-resistant CML, even those with the T3151 mutation. Hematologic and cytogenetic responses have been obtained with an acceptable safety profile, although myelosuppression remains the most common adverse effect. Omacetaxine offers a new, mutation- independent mechanism of action, addressing an unmet therapeutic need in CML treatment. Additional research is investigating its use with combination regimens and in earlier lines of treatment.