Combined analysis of the impact of second-generation BTK inhibitors on patient outcomes.

BTK inhibitors (BTKi) are highly effective in B-cell malignancies. Acalabrutinib and zanubrutinib have exhibited favorable safety profiles when compared with ibrutinib. We identified all published/presented randomized trials comparing a second-generation BTKi with ibrutinib and reconstructed individual patient-level, censored time-to-event data for adverse events to evaluate the impact of second-generation BTKi on safety outcomes including atrial fibrillation/flutter [AF], hypertension, bleeding, diarrhea, and infection. 1386 pts from ELEVATE-RR ( n  = 533), ALPINE ( n  = 652), and ASPEN ( n  = 201) trials were included in the analyses. Acalabrutinib or zanubrutinib were associated with significant reductions in cumulative event rates of AF (HR 0.28, 95% CI 0.18-0.42, p  < 0.001), bleeding (HR 0.65, 95% CI 0.52-0.81, p  < 0.001), diarrhea (HR 0.61, 95% CI 0.47-0.78, p  < 0.001), hypertension (HR 0.40, 95% CI 0.27-0.61, p  < 0.001), and infections (HR 0.83, 95% CI 0.70-0.98, p  = 0.032). In summary, zanubrutinib and acalabrutinib have a favorable safety profile among pts with r/r B-cell malignancies. These data support use of acalabrutinib or zanubrutinib as preferred BTK inhibitors for approved indications.