Molecular patterns of ibrutinib-resistant disease. A schematic representation of study findings. Sensitivity to ibrutinib is altered by histology and the presence of resistance-conferring mutations. Histologic transformation is an early event (<15 months in the study presented here), and can be de novo (clonally unrelated) or originate in the CLL clone (clonally related). Progressive CLL occurs later in the treatment course, and is frequently accompanied by BTK (red circles) and/or PLCG2 (blue circles) mutations. Multiple subclones can coexist, precede clinical progression by many months, and expand at different rates.