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.