6596 Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class, reversible, transient inhibitor of protein elongation that facilitates tumor cell death without depending on BCR-ABL signaling. Clinical activity was shown in two phase 2, open-label, multicenter studies of patients with treatment-resistant CML who had failed at least prior imatinib, many of whom were also resistant to or intolerant of dasatinib and/or nilotinib. Methods: A subset of data from the phase 2 studies included patients in chronic phase who were resistant/intolerant to ≥2 approved TKIs. Omacetaxine 1.25 mg/m2 was given subcutaneously twice daily: ≤14 consecutive days/28-day cycle for induction, ≤7 days/cycle as maintenance. Patients had never achieved or lost response to ≥2 TKIs (R group), were intolerant of ≥2 TKIs (I), or resistant to 1 and intolerant of another (R/I) were evaluated. Results: Of 81 patients (median age, 58 years), 69 were R, 7 I, and 5 R/I. Major cytogenetic response occurred in 13 (19%) in the R group (median duration not reached), 2 (29%) I (median duration 7.4 months), and 1 (20%) R/I (duration 17.7 months). For all patients, cycles of exposure and study duration were 7 cycles and 9.1 months (R); 4 cycles, 7.3 months (I); and 2 cycles, 2.3 months (R/I). Median overall survival in months were 33.9 (R), not reached (I), and 25.0 (R/I). Of 66 (81%) patients with treatment-related grade 3/4 adverse events (AEs), the most common were thrombocytopenia in 44 R, 6 I, and 4 R/I patients and neutropenia in 32 R, 4 I, and 1 R/I. Fifteen patients had an AE leading to discontinuation (10 R, 2 I, 3 R/I), primarily disease progression. There were 9 deaths (the most common were disease progression, sepsis), 8 I, 1 R/I; 2 were considered related to treatment (both sepsis). Conclusions: This subset analysis of patients with chronic-phase CML and prior therapy with ≥2 TKIs shows that omacetaxine provides efficacy and tolerability across TKI-R, I, and R/I groups. Interpretation of the I and the R/I group data was limited by small sample sizes. Support: Teva Pharmaceutical Industries Ltd.