Omacetaxine for chronic or accelerated phase CML in patients with resistance or intolerance to TKIs

Omacetaxine mepesuccinate has been granted accelerated approval for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Approval was based on response rates observed in a combined cohort of adult CML patients from 2 clinical trials. As yet, no clinical trials have verified improved disease-related symptoms or increased survival with omacetaxine treatment. The mechanism of action of omacetaxine is not fully known, but it includes inhibition of protein synthesis and activity that is independent of direct BCR-ABL binding. The agent was shown to have activity in CML patients in the pre-TKI era. In studies in vitro, omacetaxine reduces levels of the BCR-ABL oncoprotein and Mcl-1 (an anti-apoptotic BCL-2 family member), and its activity is not affected by presence of BCR-ABL mutations. It exhibits activity in animal models of wild-type and T315I-mutant BCR-ABL CML and in CML patients with the T315I mutation. The combined cohort in which efficacy of omacetaxine was assessed consisted of 111 patients (76 with CP CML and 35 with AP CML) who had received 2 or more approved TKIs and had documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); no cytogenetic response by 24 weeks (ie, 100% Philadelphia chromosome positive [Ph ] – whether lost or never achieved); no major cytogenetic response (MCyR) by 52 weeks (ie, 35% Ph – whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: grade 3 to 4 nonhematologic toxicity that did not resolve with adequate intervention; grade 4 hematologic toxicity lasting more than 7 days; or any grade 2 or higher toxicity that was unacceptable to the patient. Patients with New York Heart Association class III or IV heart disease,