Real-world clinical outcomes in patients with CLL previously treated with covalent BTKi and BCL2i regimens

● Time-to-event outcomes are worse in DR CLL vs DE and DE only CLL, indicating reduced response durability after cBTKi/BCL2i failure. Patients with chronic lymphocytic leukemia (CLL) double exposed (DE) or double refractory (DR) to covalent Bruton tyrosine kinase inhibitors (cBTKi) and B-cell lymphoma 2 inhibitors (BCL2i) have limited treatment options and poor outcomes. We evaluated real-world treatment patterns, response, and time-to-event (TTE) outcomes in patients with DE CLL (N = 264) and among the DE only (ie, DE but not DR; n =157) and DR (n = 107) subcohorts using the Flatiron Health Research Database. The DE cohort included patients who started first-line therapy for CLL on/after January 1, 2011, had a line of therapy (LOT) for CLL after DE and on/before November 30, 2022, and met other inclusion criteria. Real-world response rate (rwRR) and TTE outcomes (duration of response [rwDOR], progression-free survival [rwPFS], time to next treatment [rwTTNT], and overall survival [rwOS]), were evaluated. Most patients were retreated with a cBTKi- and/or a BCL2i-based therapy (DE, 69%; DE only, 75%; DR, 54%) as their first index LOT. rwRR was similar between groups (DE, 39%; DE only, 41%; DR, 36%), but median TTE outcomes were shorter in the DR subcohort (DR vs DE vs DE only: rwDOR, 11.5 vs 20.3 vs 26.2 months; rwPFS, 5.0 vs 8.8 vs 11.3 months; rwTTNT, 8.0 vs 13.8 vs 22.1 months; rwOS, 14.7 vs 25.2 vs 38.2 months) and shorter with each subsequent index LOT. Our results suggest an unmet need among patients with DR CLL. Future studies should continue to evaluate response durability with different treatments in DE and DR CLL populations.