Acalabrutinib (Acala) was a next-generation, highly selective, covalent Bruton tyrosine kinase (BTK) inhibitor licensed for chronic lymphocytic leukemia (CLL) patients (pts). In the primary analysis of ASCEND (median follow-up 16.1 months), Acala outperformed idelalisib (Id) plus rituximab (R) (IdR) and bendamustine (B) plus R (BR) in patients with relapsed/refractory (R/R) CLL with an acceptable tolerability profile. For a study, researchers sought to present the findings of the ASCEND trial after a 4-year follow-up period. In this multicenter, open-label, phase 3 study (NCT02970318), patients with R/R CLL were given either oral (PO) acala 100 mg BID until progression or unacceptable toxicity or the investigator’s (INV) choice of IdR (Id: 150 mg PO BID until progression or unacceptable toxicity; R: 375 mg/m2 x1 then 500 mg/m2 IV [8 total infusions]) or BR (B: 70 mg /m2 IV; R: 375 mg/m2 x1 then 500 mg/m2 IV [6 cycles]). Investigators looked at progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and safety. A total of 310 points (Acala, n=155; IdR, n=119; BR, n=36) were randomised (median age 67 years; del(17p) 15%, unmutated IGHV 74%, Rai stage 3/4 42%). At 46.5 months (Acala) and 45.3 months (IdR/BR), Acala significantly extended INV-assessed PFS compared to IdR/BR (median not reached [NR] vs 16.8 months; P<0.0001); 42-month PFS rates for Acala were 62% vs 19% for IdR/BR. The median PFS in patients with del(17p) was NR (Acala) versus 13.8 mo (IdR/BR; P<0.0001). PFS was NR (Acala) vs 16.2 mo (IdR/BR; P<0.0001) in patients with unmutated IGHV. The median OS was NR; 42-month OS rates were 78% (Acala) versus 65% (IdR/BR). ORR (Acala) was 83% vs 84% (IdR/BR) (ORR + partial response with lymphocytosis: 92% [acala] vs 88% [IdR/BR]). In 23% of Acala, 67% of IdR, and 17% of BR patients, adverse events resulted in treatment cessation. All-grade atrial fibrillation/flutter (8% versus 3%), all-grade hypertension (8% vs 5%), all-grade major haemorrhage (3% vs 3%), and grade 3 infections were all events of clinical importance (Acala vs IdR/BR) (29% vs 29%). Acala maintained efficacy and a consistent tolerability profile in R/R CLL after four years of follow-up compared to standard-of-care regimens.