title: 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.affiliation: Department of Leukemia, UT MD Anderson Cancer Center, Houston, TX 77030, USA. jcortes@mdanderson.org
authors.forename: J
authors.initials: J
authors.lastname: Cortes
authors.forename: R
authors.initials: R
authors.lastname: Digumarti
authors.forename: P M
authors.initials: PM
authors.lastname: Parikh
authors.forename: M
authors.initials: M
authors.lastname: Wetzler
authors.forename: J H
authors.initials: JH
authors.lastname: Lipton
authors.forename: A
authors.initials: A
authors.lastname: Hochhaus
authors.forename: A R
authors.initials: AR
authors.lastname: Craig
authors.forename: A-C
authors.initials: AC
authors.lastname: Benichou
authors.forename: F E
authors.initials: FE
authors.lastname: Nicolini
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D016903:Drug Monitoring; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006248:Harringtonines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006410:Hematopoiesis / Q000187:drug effects; D000077863:Homoharringtonine; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects; D007279:Injections, Subcutaneous; D015466:Leukemia, Myeloid, Chronic-Phase / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D060046:Maintenance Chemotherapy / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D000077863:Homoharringtonine; D011505:Protein-Tyrosine Kinases