Jennifer Woyach, MD, The Ohio State University, Columbus, OH, discusses the mechanisms of resistance to acalabrutinib, a selective, second-generation irreversible Bruton’s Tyrosine Kinase inhibitor (BTKi), which has shown outstanding clinical activity in chronic lymphocytic leukemia (CLL). It is known that acquired resistance to ibrutinib, a first-generation BTKi, is mediated most commonly by C481S mutations in BTK, decreasing binding affinity. This study shows for the first time that CLL relapse following acalabrutinib is mediated predominantly by mutations in BTK, similarly to ibrutinib. This interview took place at the American Society of Hematology (ASH) 2019 Annual Meeting and Exposition in Orlando, FL.