title: Resistant chronic myeloid leukemia beyond tyrosine-kinase inhibitor therapy: which role for omacetaxine?
abstract: The therapeutic armamentarium of chronic myeloid leukemia (CML) has been considerably improved after the introduction of first- and second-generation tyrosine-kinase inhibitors (TKIs). Accordingly, the natural history of the diseases has changed, and patients in complete molecular response now have the same life expectancy of their healthy coetaneous. Notwithstanding these results, ∼ 20 - 30% of patients do not respond optimally to TKIs therapy, and most of these patients are potential candidates to progress toward the accelerated or blastic phase of the disease. Unfortunately, patients who become resistant to both first- and second-generation TKIs develop BCR-ABL kinase domain mutations, against which TKIs have extremely low cross-activity. In particular, none of the TKIs, with the exception of ponatinib, has significant activity against T315 mutation, which is estimated to be present in ∼ 15 - 20% of patients carrying BCR-ABL mutations. The use of omacetaxine mepesuccinate/homoharringtonine for the treatment of TKI-resistant CML patients regained interest due to its mechanism of action independent of binding to the ATP-binding pocket. Therefore, the activity of this compound is independent from the presence of BCR-ABL1 mutations, which makes it an attractive option for the treatment of CML patients after TKI failure.
authors.affiliation: Hematology & Hematopoietic Stem Cell Transplant Center, AORMN MARCHE NORD , Via Lombroso, 1 - 61100, Pesaro , Italy +39 0721 364039 ; +39 0721 364036 ; giuseppe.visani@ospedalimarchenord.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Visani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Isidori
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006248:Harringtonines / Q000627:therapeutic use*; D000077863:Homoharringtonine; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D006248:Harringtonines; D047428:Protein Kinase Inhibitors; D000077863:Homoharringtonine; D011505:Protein-Tyrosine Kinases