Analysis of the Sub-Clonal Origins of Compound Mutations in Patients with Refractory Ph+ Malignancies Treated with Ponatinib

Background: Ponatinib is a tyrosine kinase inhibitor (TKI) with potent activity against BCR-ABL1 and all single resistance mutants. In the Phase 2 PACE study (NCT01207440), ponatinib induced high rates of major hematological response (MaHR) and major cytogenetic response (MCyR) in BP-CML (31% and 23%) and Ph+ ALL (41% and 47%) patients (pts), even though 91% of pts had received at least 2 prior TKIs. However, the median progression free survival was only 4 months for BP-CML and 3 months for Ph+ ALL (Cortes JE, et al. N Engl J Med2013). Previous studies have shown that certain compound mutations can cause resistance to ponatinib (Zabriskie et al. Cancer Cell2014), but such mutations were found to be extremely rare in CP-CML pts from the PACE trial despite being heavily pre-treated (Deininger MW, et al. Blood2016). Here we utilize a multi-level sequencing strategy that combines Sanger Sequencing (SS), Next Generation Sequencing (NGS), and single molecule Duplex Sequencing (DS), which is orders of magnitude more sensitive than NGS, to profile the mutational mechanisms that may account for the survival outcomes observed in BP-CML/Ph+ ALL pts treated with ponatinib in PACE.