Subcutaneous Omacetaxine in Chronic or Accelerated Chronic Myeloid Leukemia Resistant to Two or More Tyrosine-Kinase Inhibitors Including Imatinib,

Omacetaxine is a first-in-class, reversible, transient inhibitor of protein elongation that does not depend on BCR-ABL binding. By blocking ribosomal function, the drug decreases intracellular levels of several antiapoptotic regulatory proteins, inducing antitumor activity via apoptosis [Pérez-Galán P et al. Blood 2007;109:4441–9]. Omacetaxine had clinical activity and was well tolerated in two phase 2, open-label, multicenter studies, including 1 in chronic myeloid leukemia (CML) patients with T315I mutation who had failed prior imatinib [Cortes et al, EHA 2011 Abstract 1012] and the second in CML patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs) [Cortes et al, ASH 2009 Abstract 861].

This analysis included patients with CML-chronic phase (CML-CP) and CML-accelerated phase (CML-AP) from either of the two phase 2 studies mentioned above. All patients had previously been treated with ≥2 TKIs (including imatinib), to which they had shown resistance (eg, via point mutations) or intolerance. All patients received omacetaxine 1.25 mg/m² subcutaneously twice daily for 14 consecutive days every 28 days for induction and for 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factors could be administered if necessary. The primary endpoints for CML-CP patients were major cytogenetic response (MCyR) or complete hematologic response (CHR), and for CML-AP patients they were major hematologic response (MHR) or no evidence of leukemia (NEL). Patients were followed for survival after omacetaxine discontinuation.

Of 122 patients, 81 had CML-CP (median age 59 years; range 26–83) and 41 had CML-AP (median age 63 years; range 23–83). All patients had previously received imatinib; 85% of CML-CP patients and 93% of CML-AP patients had received dasatinib, 59% and 63% nilotinib, and 14% and 17% other antineoplastic agents other than TKIs, respectively. Sixty-nine patients had shown resistance to ≥2 TKIs, 7 showed intolerance, and 5 resistance to 1 and intolerance to another. Previous treatments ended a median 1.3 (range 0.2–28) months prior to the study in CML-CP patients and a median 2.1 (range -4 to 33) months in CML-AP patients. Median on-study exposure to omacetaxine was 7.4 (range 0–39) months among CML-CP and 1.9 (0–30) months among CML-AP patients. In the CML-CP group, 16 patients (20%) achieved a MCyR (8 [10%] complete, 8 [10%] partial); the median duration of MCyR was 18 months (range 4 to ongoing). In addition, 4 (5%) had a minor cytogenetic response. Fifty-six (69%) achieved CHR with a median response duration of 12.2 months (range 8–26); median onset time was 0.7 (95% CI, 0.5–1.2) months. The median overall survival was 34 months.

In the CML-AP group, 11 patients (27%) had a MHR, including 10 (24%) with CHR and 1 (2%) with NEL; the median duration of MHR was 9 months (range 4–14). In addition, 2 (5%) achieved a return to chronic phase and 3 (7%) had hematologic improvement. Three (7%) patients had a minor and 3 (7%) had a minimal cytogenetic response. The median overall survival was 16 months. The most common cause for discontinuation was disease progression: 5 (6%) of CML-CP and 5 (12%) of CML-AP patients. Among CML-CP and CML-AP patients, 12% and 24%, respectively, discontinued treatment due to adverse events (AEs) of all types, excluding disease progression. The most common serious AEs (>5% in either group) for CML-CP and CML-AP patients, respectively, were febrile neutropenia (7.4%, 12.2%), bone marrow failure (11.1%, 0), and thrombocytopenia (11.1%, 7.3%), excluding disease progression. The most common (>15% in both groups) grade 3/4 hematologic toxicities for CML-CP and CML-AP patients, respectively, were anemia (37%, 34%), neutropenia (47%, 22%), and thrombocytopenia (67%, 46%). The most frequent (≥5% in either group) nonhematologic grade 3/4 AEs in CML-CP and CML-AP patients, respectively, were general disorders (eg, aplasia, fatigue, generalized edema) (9%, 5%), infections (5%, 2%), metabolism and nutrition (0, 10%), and respiratory (1%, 5%).

Patients with CML who had failed previous treatment with ≥2 TKIs showed clinically meaningful response to omacetaxine therapy. Omacetaxine was well tolerated in this population.

Cortes:ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Deciphera: Research Funding. Off Label Use: Omacetaxine is an investigational drug. Nicolini:Bristol Myers Squibb France: Consultancy, Speakers Bureau; Norvartis Pharma France: Consultancy, Research Funding, Speakers Bureau. Wetzler:Novartis Pharmaceuticals Corporation: Consultancy; ChemGenex (Cephalon): Consultancy, Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding. Akard:Novartis: Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau. Craig:Cephalon, Inc.: Employment. Nanda:Cephalon, Inc.: Employment. Dial:Cephalon, Inc.: Employment. Benichou:Cephalon, Inc.: Employment. Cairati:Cephalon, Inc.: Employment. Baccarani:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Oncology: Consultancy, Honoraria. Kennealey:Cephalon, Inc.: Employment. Kantarjian:ChemGenex: ChemGenex is now Cephalon, Inc., Employment.