title: Subcutaneous omacetaxine mepesuccinate in patients with chronic-phase chronic myeloid leukemia previously treated with 2 or more tyrosine kinase inhibitors including imatinib.
abstract: BACKGROUND
  Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).
  
  
  METHODS
  Data were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m(2) twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point.
  
  
  RESULTS
  Eighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months - not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%).
  
  
  CONCLUSIONS
  Omacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: jcortes@mdanderson.org.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.forename: Luke
authors.initials: L
authors.lastname: Akard
authors.forename: Adam
authors.initials: A
authors.lastname: Craig
authors.forename: Nisha
authors.initials: N
authors.lastname: Nanda
authors.forename: Annie-Claude
authors.initials: AC
authors.lastname: Benichou
authors.forename: Janis
authors.initials: J
authors.lastname: Leonoudakis
authors.forename: H Jean
authors.initials: HJ
authors.lastname: Khoury
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006248:Harringtonines / Q000008:administration & dosage* / Q000009:adverse effects; D000077863:Homoharringtonine; D006801:Humans; D000068877:Imatinib Mesylate; D055104:Infusions, Subcutaneous; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D006248:Harringtonines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate
keywords: Dasatinib; Homoharringtonine; Intolerance; Nilotinib; Resistance