Associations Between Baseline Mutation Status and Response to Treatment with Omacetaxine Mepesuccinate in Heavily Pretreated Patients with Chronic Myeloid Leukemia
Authors: Lipton Jeffrey H. , Nicolini Franck E. , Wetzler Meir , Akard Luke , Baccarani Michele , Kantarjian Hagop M. , Craig Adam , Cortes Jorge E 
Published: October 2019

Abstract
Abstract 4433

Background
Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class cephalotaxine and is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine reduces levels of multiple oncoproteins, including Bcr-Abl, and induces apoptosis in leukemic stem cells by blocking the initial step of protein translation at the level of the ribosome. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML). Patients with a history of the T315I mutation who failed prior imatinib were enrolled in the first study (CML202). Patients were enrolled in the second study (CML203) if they had resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). Point mutations occur frequently in CML patients who develop resistance to imatinib. This is a post hoc analysis of responses to omacetaxine in patients with any phase CML by mutational status.

Methods
Data from patients with CML in chronic phase (CP), accelerated phase (AP), or blast phase (BP) were included from the two phase 2 studies. Omacetaxine 1.25 mg/m2was administered subcutaneously twice daily for 14 consecutive days every 28 days for induction and the same dosage for 7 days every 28 days as maintenance. An exploratory analysis was conducted to elucidate associations between mutation status and complete hematologic response (CHR) or major cytogenetic response (MCyR) following omacetaxine treatment.

Results
Among CP, AP, and BP patients, grade 3/4 hematologic toxicities were thrombocytopenia (in 89/105, 43/49, and 43/44 patients, respectively), neutropenia (86/106, 35/49, 36/44), leukopenia (76/106, 30/49, 29/44), and anemia (66/107, 39/49, 36/44). Common grade 3/4 nonhematologic adverse events included fatigue (5/108, 5/51, and 2/44 patients, respectively) and pneumonia (3/108, 4/51, and 2/44). Seventy-six deaths occurred during long-term follow-up (33, 24, 19); 8 were treatment-related (5, 2, 1), most commonly due to sepsis (n=3).
The pooled baseline mutational analysis included 203 CML patients (108 CP, 51 AP, and 44 BP). Unknown mutations were noted in 24%, 25%, and 32% of CP, AP and BP patients, respectively. Mutations were identified in 52%, 51%, and 52% while no mutation status was recorded for 24%, 25%, and 16% of CP, AP, and BP patients, respectively. T315I was the most frequently identified mutation (Table), occurring in 36%, 24%, and 39% of patients, respectively. Multiple mutations, which include individual mutations listed separately, were detected in 12% CP, 14% AP, and 7% BP patients.
Among patients with CP or AP CML, CHR rate was high in the presence of the T315I mutation. MCyR rates for CP patients were similar for patients with or without mutations but appeared to be relatively lower among patients with multiple mutations. Among AP patients, MCyR only occurred in those without mutations.

Conclusions
Point mutations, particularly T315I, were common in this heavily treated population of CML patients although T315I may be overrepresented due to CML202 inclusion criteria. Efficacy of omacetaxine, as measured by rates of CHR and MCyR, appeared to be largely independent of the presence or absence of point mutations. However, interpretation of these results is limited by small sample sizes in many of the groups.
Support: Teva Pharmaceutical Industries Ltd.

Disclosures:
Off Label Use: Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a protein synthesis inhibitor that does not depend on direct binding of Bcr-Abl. Omacetaxine has shown clinical activity in 2 studies of chronic myeloid leukemia (CML), one in patients with a history of the T315I Bcr-Abl mutation and the other in patients failing at least 2 tyrosine kinase inhibitors. Nicolini:BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler:BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Akard:Celgene: Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Eisai: Speakers Bureau; Pfizer: Research Funding; Merck: Research Funding; Ariad: Research Funding; Teva: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Baccarani:Teva: Research Funding. Kantarjian:ChemGenex (Teva): Research Funding. Craig:Teva: Consultancy. Cortes:Chemgenex (Teva): Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Deciphera: Research Funding.