Subcutaneous omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class cephalotaxine. Omacetaxine 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. Omacetaxine has shown clinical activity and adequate tolerability in two phase 2, open-label, international, multicenter studies in patients with chronic myeloid leukemia (CML): the first in patients with history of T315I mutation who had failed prior imatinib and the second in patients with resistance or intolerance to ≥2 tyrosine kinase inhibitors (TKIs). This is a pooled analysis of the efficacy and safety data of omacetaxine in patients with CML in the blast phase (BP).
Data from patients with CML-BP were included from two phase 2 studies. All patients received omacetaxine 1.25 mg/m2 subcutaneously twice daily for up to 14 consecutive days every 28 days for induction and the same dosage for up to 7 days every 28 days as maintenance. The number of consecutive days of dosing could be adjusted, as clinically indicated. Recombinant growth factor support was allowed in the event of febrile neutropenia. The primary outcome measures were major hematologic response (MaHR) and major cytogenetic response (MCyR). MaHR was defined as complete hematologic response (CHR) lasting ≥4 weeks, no evidence of leukemia, or return to chronic phase. MCyR included confirmed or unconfirmed complete or partial response. Secondary endpoints included duration of response, time to disease progression, overall survival and safety.
Forty-four patients with CML-BP (median age 53.5 years [range, 19–68]) received treatment with omacetaxine. Forty-two patients (96%) had ECOG status ≤2. All but 1 patient had prior treatment with imatinib; 5 (11%) patients received imatinib only, 20 (45%) received 2 approved TKIs (imatinib, dasatinib, or nilotinib), and 19 (43%) were treated with all 3 approved TKIs. Most common non-TKI agents included hydroxyurea in 18/44 (41%), anthracyclines and related agents in 17 (39%), cytarabine in 14 (32%), and interferons in 11 (25%). Mutation analysis was not performed per protocol; however, point mutations were detected in 23 patients, and 17 (74%) of these had the T315I mutation. No mutations were identified in 7 patients and 14 were not assessed for mutations.
The median number of cycles of omacetaxine administered was 2 (range 1–12) with a median duration of exposure of 1.5 months (range 0–13.8). Four patients (9%) had a MaHR (3 with CHR and 1 returned to chronic phase); additional 2 patients had hematologic improvement as a best response. No patient achieved MCyR; 3 patients (7%) achieved a minimal cytogenetic response. Median duration of MaHR was 1.7 months (range 1.7–4.9 months). Median survival was 3.5 months (95% CI 2.2–4.5); in 4 patients with MaHR, median survival was not reached as of >1 year of follow-up by Kaplan-Meier analysis (95% CI 2.4 to not reached) versus 3.5 months (95% CI 2.2–3.9) in patients without MaHR (Figure). Median time to disease progression was 2.2 months (95% CI 1.5–2.9). Grade 3/4 laboratory hematologic toxicities included thrombocytopenia (43/44 patients), anemia (36/44), neutropenia (36/44), and leukopenia (29/44), with most of the thrombocytopenia and neutropenia toxicities occurring in earlier cycles and attenuating in later cycles. The most common (≥5%) grade 3/4 nonhematologic AEs were hypercalcemia and bone pain (4/44 each), followed by confusional state (3/44). The most common reasons for discontinuation were progressive disease (21 patients) and death (14 patients); 2 patients discontinued due to AEs. One patient discontinued due to transfer for stem cell transplantation (7 cycles received on study over 6.7 months). Nineteen deaths occurred on study and 19 during follow-up; disease progression was the most common cause (25/38). One death was deemed related to the study drug (sepsis).
Among heavily pretreated patients with CML-BP who had failed prior TKI therapy, omacetaxine demonstrated limited activity, although 13% of patients had hematologic improvement, 2 patients had responses with duration longer than one year. Most grade 3/4 events were hematologic; grade 3/4 nonhematologic AEs were less common.
Support: Teva Pharmaceutical Industries Ltd.
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. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex (Teva): Consultancy, Research Funding; Deciphera: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Wetzler:BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Baccarani:Teva: Research Funding. Douer:Teva: Consultancy. Craig:Teva: Consultancy. Kantarjian:ChemGenex (Teva): Research Funding. 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.
Asterisk with author names denotes non-ASH members.