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.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Harringtonines/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Protein Synthesis Inhibitors/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Bone Marrow Cells/drug effects , Bone Marrow Cells/pathology , Drug Monitoring , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Female , Harringtonines/administration & dosage , Harringtonines/adverse effects , Hematopoiesis/drug effects , Homoharringtonine , Humans , Induction Chemotherapy/adverse effects , Injections, Subcutaneous , Leukemia, Myeloid, Chronic-Phase/blood , 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-Tyrosine Kinases/antagonists & inhibitors , Survival Analysis , Young AdultABSTRACT
The authors give biological reference figures obtained from 106 fetuses that were sampled in utero between the 20th and 34th week of amenorrhoea. These fetuses were considered to be normal because there was no clinical or ultrasound evidence of an abnormality. Furthermore the biological values sought in antenatal testing and the absence of all pathology in the first year of life, confirmed that these were normal fetuses. The result has been expressed as a global figure for all 106 fetuses; then they have been divided up according to the gestational age groups (20-23, 24-27, and 28-34 weeks of amenorrhoea). These biological reference values and their changes as the age of the fetuses advanced are discussed and compared with the figures reported in the literature.