Correlation of clinical response to BMS-354825 with BCR-ABL mutation status in imatinib-resistant patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-associated acute lymphoblastic leukemia (Ph+ ALL)

Abstract

6521 Background: Relapse of CML on imatinib is most often associated with point mutations in the BCR-ABL kinase domain. BMS-354825 is a novel ABL kinase inhibitor with ≥ 300-fold greater potency than imatinib and preclinical activity against 14 of 15 imatinib resistant BCR-ABL mutants tested. Unlike imatinib, BMS-354825 binds the ABL kinase domain in both active and inactive conformations, and is thus predicted to have significant activity in most imatinib-resistant CML and Ph+ ALL cases. Methods: CA180002 is a phase I, dose-escalation study in CML and Ph+ ALL patients resistant or intolerant to imatinib. Prior to therapy, peripheral blood samples were collected for mutation analysis for correlation with response. Response was assessed by standard methods. Sixty-three patients are currently evaluable [chronic phase=36, accelerated phase=8, blast phase/Ph+ ALL=19]. Results: Seventeen different imatinib-resistant point mutations in the BCR-ABL kinase domain were identified in 67% of patients prior to therapy. Complete hematologic remission has been observed in patients harboring each of these mutations except T315I (5), F317L (1), and D276G (1). The two patients with F317L and D276G have had partial responses and remain on study. The T315I mutation is highly resistant to BMS-354825 in experimental systems. Nine patients have gone off study due to progressive disease. Of these, three had T315I detected prior to treatment and two patients had the T315I mutation at the time of disease progression. Assessment of BCR-ABL kinase inhibition by analysis of phospho-CRKL in patient samples was correlated with response, and loss of BCR-ABL kinase inhibition was correlated with relapse. Conclusions: Clinical activity of BMS-354825 in imatinib-resistant CML and Ph+ ALL is observed in patients with a wide range of imatinib-resistant BCR-ABL kinase domain mutations. The exception to date is T315I, which is cross-resistant to both drugs, as predicted from preclinical studies. This works demonstrates the utility of molecular assessment of tumor early in the clinical evaluation of a targeted inhibitor. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb