Long-Term Follow-up of Ongoing Patients in 2 Studies of Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is an investigational, first-in-class cephalotaxine, 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. It has shown clinical activity and adequate tolerability in two phase 2, open-label studies of chronic myeloid leukemia (CML), the first in patients with a history of the T315I Bcr-Abl mutation (enrolled September 2006 through March 2010) and the second in patients with resistance or intolerance to ≥2 approved tyrosine kinase inhibitors (TKIs; enrolled March 2007 through June 2009). This ad hoc analysis presents the efficacy and safety results of patients in the phase 2 studies who remained on omacetaxine as of March 31, 2012.

Efficacy and safety data were pooled from patients with CML chronic phase (CML-CP) and CML accelerated phase (CML-AP) who received omacetaxine in either of the phase 2 studies and had not discontinued omacetaxine as of March 31, 2012. Omacetaxine 1.25 mg/m²was given subcutaneously twice daily up to 14 consecutive days per 28-day cycle for induction and at the same dosage for up to 7 days/cycle as maintenance.

Of the 203 patients enrolled in the 2 studies (108 CML-CP, 51 CML-AP, and 44 CML blast phase), 9 CML-CP patients (median 35 cycles [range 26–53]) and 2 CML-AP patients (median 20.5 cycles [range 19–22]) continue to receive omacetaxine. Median age of ongoing CML-CP patients at baseline was 61 years (range 45–73); 7 were male. Median age of ongoing CML-AP patients was 58 years (range 48–67); all were male. For CML-CP patients, the median number of dosing days was 137 (range 68–342) over a median of 35 cycles (range 26–53); the 2 CML-AP patients had 189 and 277 dosing days during 19 and 22 cycles, respectively. Other baseline clinical characteristics are presented in the Table.

Seven of the CML-CP patients achieved MCyR, including 6 complete responses. One CML-CP patient achieved a minimal cytogenetic response and 1 had no response. No CML-AP patient achieved MCyR. Time to onset of MCyR for the CML-CP patients were <3 months (n=2), 3 to <6 months (n=2), and 6 to <12 months (n=3). In the 7 patients with MCyR, duration of response to date is ≥6 to <12 (n=3), ≥12 to <18 (n=2), and ≥18 months (n=2); none lost response.

Six CML-CP patients were in CHR at baseline and 3 achieved CHR within 3 months. One CML-AP patient achieved CHR at <3 months and 1 only had hematologic improvement. Eight of the 9 CML-CP patients and 1 CML-AP patient remained in CHR at time of analysis, whereas 1 CML-CP patient lost response in ≥6 to <12 months (patient had minimal cytogenetic response). At the last recorded cycle, the number of dosing days for CML-CP patients ranged from 1–12 days and 7–15 days in CML-AP patients; number of days of treatment delay ranged from 0–4 days in CML-CP patients and 0–33 days in the 2 CML-AP patients.

All patients had at least 1 AE and 1 serious AE. The most common AEs were anemia (11/11), thrombocytopenia (9/11), neutropenia (6/11), nausea (7/11), diarrhea or fatigue (5/11 each), and headache (4/11). Grade 3/4 AEs occurred in 10 (91%) patients. The most common were hematologic: thrombocytopenia (79%

A subset of heavily pretreated patients with CP or AP CML who participated in phase 2 studies of omacetaxine were able to continue omacetaxine for up to 53 cycles and experience durable major cytogenetic and hematologic responses. Grade 3/4 AEs were primarily hematologic and consistent with the known safety profile of omacetaxine.

Kantarjian:ChemGenex (Teva): Research Funding. 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. Baccarani:Teva: Research Funding. Nicolini:BMS: Research Funding, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Teva: Speakers Bureau. Wetzler:Teva: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Akard:Merck: Research Funding; Pfizer: Research Funding; Eisai: Speakers Bureau; Millenium: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding; Teva: Research Funding. Legros:Celgene: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Craig:Teva: Consultancy. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding.