High-Resolution Analysis of the Relationship Between Ponatinib Dose and Molecular Response in CP-CML Patients in the PACE Trial

Abstract

Understanding the relationship between dose and efficacy is a critical step in optimizing the benefit-risk ratio of therapeutic agents. Ponatinib, a potent pan-BCR-ABL TKI, induced major cytogenetic and molecular responses in heavily pretreated CP-CML patients in the PACE trial. Investigation of the dose-response relationship (45mg starting dose) revealed that induction of MCyR was dose-dependent and that responses were maintained upon dose reduction (to 15 or 30mg). To further explore the dose-efficacy relationship of ponatinib, we developed a novel approach to associate drug exposure with changes in BCR-ABL transcript levels. The method, BCR-ABL Response-Dose association (BARD), enables a higher-resolution view of the dose-response relationship in CML than endpoint analyses because of the high sensitivity, broad dynamic range, and frequency of molecular response assessments.