In vivo activity of AMN107, as selective Bcr-Abl kinase inhibitor, in murine leukemia models

Abstract

6522 Background: The Bcr-Abl oncoprotein has unregulated tyrosine kinase activity and causes chronic myelogenous leukemia (CML). Imatinib, a Bcr-Abl kinase inhibitor, is an effective therapy. However in advanced CML and Ph+ acute lymphocytic leukemia, patients may relapse due to emergence of imatinib-resistant forms of mutant Bcr-Abl kinases, prompting the search for new treatments. AMN107 is a novel kinase inhibitor, affecting both the non-mutated p210 Bcr-Abl and many of the mutant forms of Bcr-Abl. Methods: Two murine models of Bcr/Abl leukemia were studied. AMN107, imatinib, or vehicle were administered orally (75 mg/kg q.d.) following injection of p210 Bcr-Abl or imatinib-resistant E255V-Bcr-Abl 32D cells to Balb/c mice, or after injection of p210, E255V- or M351T-Bcr-Abl transduced primary bone-marrow cells to irradiated Balb/c mice. Results: AMN107 (75 mg/kg p.o. in 10%:90% NMP-PEG300) was well absorbed in mice, with mean plasma levels of 25 μM after 24 h (AUC0–24h 641 h.μmol.L). In the p210–32D Balb/c study, vehicle-treated animals (19/20) developed a lethal leukemic disease (survival range 15–36 days) whereas AMN107, administered over 16 days, resulted in the protection of 15/20 animals for 100 days; median spleen weight in AMN107-treated animals were normal (0.085 g; n = 17) compared to that of controls (0.51 g; n = 20). AMN107 also gave a significant reduction in disease burden in the E255V-32D study. In the primary bone-marrow Balb/c model, vehicle-treated animals (12/12) developed splenomegaly and leukocytosis and were sacrificed by day 16, whereas AMN107, administered from day 8, significantly protected animals until the end of the study (day 20). Similar effects were seen with E255V and M351T transduced bone-marrow cells. Conclusions: These studies indicate that AMN107 can protect mice from Bcr-Abl induced disease, including leukemias induced by imatinib-resistant mutants of Bcr-Abl, and that it may have clinical utility in patients with Bcr-Abl+ leukemias. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma AG Novartis Pharma AG