Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors.

Abstract

Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m² twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.

• Authors: J Cortes, R Digumarti, P M Parikh, M Wetzler, J H Lipton, A Hochhaus, A R Craig, A-C Benichou, F E Nicolini, H M Kantarjian, Omacetaxine 203 Study Group
• Journal: American journal of hematology (Am J Hematol) Vol. 88 Issue 5 Pg. 350-4 (May 2013) ISSN: 1096-8652 [Electronic] United States
• PMID: 23468307 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Harringtonines
• Protein Kinase Inhibitors
• Protein Synthesis Inhibitors
• Homoharringtonine
• Protein-Tyrosine Kinases

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, therapeutic use)
• Antineoplastic Agents, Phytogenic (administration & dosage, adverse effects, therapeutic use)
• Bone Marrow Cells (drug effects, pathology)
• Drug Monitoring
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Female
• Harringtonines (administration & dosage, adverse effects, therapeutic use)
• Hematopoiesis (drug effects)
• Homoharringtonine
• Humans
• Induction Chemotherapy (adverse effects)
• Injections, Subcutaneous
• Leukemia, Myeloid, Chronic-Phase (blood, drug therapy, pathology)
• Maintenance Chemotherapy (adverse effects)
• Male
• Middle Aged
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Protein Synthesis Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Survival Analysis
• Young Adult