Bosutinib is safe and active in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to imatinib and other tyrosine kinase inhibitors

Abstract

Background: Bosutinib (SKI-606), is an orally bioavailable dual Src/Abl inhibitor, 200 times as potent as imatinib, with minimal inhibitory activity against platelet-derived growth factor receptor or c-kit. Method: The phase II portion of a Phase I/II study to investigate the efficacy and safety of bosutinib in (pts) with CP CML who failed imatinib is ongoing. Results: We report preliminary data for 152 pts, median duration of treatment 2.82 mos (range 0.03-19.5 mos). Prior therapy in addition to imatinib, included interferon (58 pts), dasatinib and/or nilotinib (37 pts), and stem cell transplant (8 pts). Among pts who failed imatinib, 116 (76%) were imatinib-resistant and 36 (24%) intolerant. Of 38 pts evaluable for hematological response, 34 (89%) had complete response (CHR). 23/56 (41%) evaluable pts achieved a major cytogenetic response (MCyR), 17 (30%) of which were complete (CCyR). Of 58 pts evaluable for molecular response, 19 (33%) achieved a major molecular response, 11 (19%) of which were complete. Among pts with prior nilotinib or dasatinib exposure, 10/13 (77%) achieved CHR, 2/10 (20%) MCyR and 4/ 25 (16 %) major molecular response. 19 different mutations were found in 37 pts of 104 tested. CHR occurred in 2/2 pts with P-loop, 9/13 with non-P-loop and 23/26 with no mutations; MCyR occurred in 2/5 pts, 8/17 and 13/31 pts, respectively. The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), usually grade 1-2, manageable and improved spontaneously after 3- 4 weeks. Grade 3-4 non-hematologic toxicities (>5% of pts) were diarrhea (n=10, 7%) and rash (n=10, 7%). Grade 3-4 hematologic laboratory abnormalities were: thrombocytopenia (n=21, 14%), neutropenia (n=13, 9%), and anemia (2 pts, 1%). Other grade 3-4 laboratory abnormalities (>5% of pts,) included increased ALT (n=10, 7%) and hypophosphatemia (n=11, 7%). Conclusion: Bosutinib is an active treatment for pts with chronic phase CML who failed prior imatinib or other TKI therapy, including patients with a wide variety of Bcr-Abl kinase domain mutations. Bosutinib demonstrated a favorable toxicity profile with minimal hematologic toxicity.