How do you approach treatment for a fit patient with unmutated CLL who has progressed after BTKi and venetoclax containing regimens in the first and second line?   

Original answer: February 10, 2023 This is a tough situation and we are seeing increasing number of patients who have failed both BTKi and BCL2i. Clinical trial enrollment with non covalent BTKi, or other novel strategies including CAR T cell therapy should be considered. PI3K inhibitors are also a...

This is a very challenging situation and represents a major area of unmet need in CLL. I would definitely favor the use of a novel agent in the clinical trial setting if available - for example, pirtobrutinib has demonstrated very good efficacy in this group (median PFS 16.8 months). I would al...

Agree with clinical trials, Pirtobrutinib, or cellular therapy. If these options are not possible, a combination of BTKi and Venetoclax can be considered. A recent paper (below) showed encouraging activity in this patient population. Hyak et al., PMID 35834733