Development of resistance against ibrutinib in CLL. Treatment of CLL patients with ibrutinib has to be stopped because of development of clonally nonrelated aggressive lymphoma (Richter transformation), Richter transformation of a CLL subclone (both mostly occurring within 12 to 18 months of treatment initiation), progressing CLL concurring with acquisition of BTK and/or PLCG2 mutations (mostly occurring after 12 to 18 months of treatment), and possibly late progression in which no mutations of BTK or PLCG2 can be detected. The figure has been adapted from Figure 5 in the article by Ahn et al that begins on page 1469.