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

Am J Hematol. 2013 May;88(5):350-4. doi: 10.1002/ajh.23408. Epub 2013 Mar 7.

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.

Trial registration: ClinicalTrials.gov NCT00462943.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Associated data

  • ClinicalTrials.gov/NCT00462943