A patient with relapsed and refractory chronic lymphocytic leukaemia with Richter transformation was treated with chimeric antigen receptor (CAR)-modified T cells targeted for CD19 but later relapsed with a clonally related plasmablastic lymphoma. The loss of most routine markers of pre-plasma cell or B lymphoid differentiation (including CD19) highlights the ability of such mature lymphomas to evade lineage-specific targeted immunotherapy by differentiating along pathways comparable to their normal cellular counterparts. Molecular genetic evaluation demonstrated multiple independent lines of CD19-negative disease that eventually evolved in this single patient. Such plasticity represents potential challenges for antigen-directed CAR-T cell therapy, while serving as a testament to the selective pressure exerted by these engineered T cells over time.