Targeted therapies have substantially altered the natural history of chronic lymphocytic leukemia (CLL). Venetoclax, an inhibitor of BCL2 apoptosis regulator (BCL2), shows considerable efficacy, including in patients who have relapsed after ibrutinib.1 In the ibrutinib-refractory setting, overall response rate to venetoclax is 65%, with median progression-free survival of 23.5 months.1 This progression-free survival is considerably lower than in patients not previously treated with ibrutinib,2 suggesting potential distinct resistance mechanisms in this population.