Non-covalent BTK inhibitors like pirtobrutinib are currently approved for use after covalent BTK inhibitors fail. Moving them to the frontline setting, as studied in BRUIN-313, disrupts the established treatment pathway and creates uncertainty for managing relapsed disease, as the standard 'next step' is removed.
The BRUIN-313 trial successfully compared pirtobrutinib to bendamustine-rituximab (BR). However, BR is no longer the frontline standard of care. This 'straw man' comparator makes it difficult to position pirtobrutinib against current preferred treatments like other BTK inhibitors or venetoclax regimens, limiting immediate clinical applicability.
A key clinical nuance in CLL is that not all prognostic markers are static. The IGHV mutation status remains unchanged, requiring a one-time test. However, chromosomal abnormalities like deletion 17p can evolve, necessitating re-evaluation at each relapse to guide subsequent therapy choices and adapt the treatment strategy.