Background: Acalabrutinib (A) is a next-generation Bruton tyrosine kinase inhibitor approved for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Bendamustine (B) + rituximab (R) is used for treatment-naive (TN) and R/R MCL. We present updated data on safety and efficacy of ABR in patients (pts) with TN or R/R MCL. Methods: Eligible adults received ABR in this phase 1b study (NCT02717624) as follows: ABR for 6 28-d cycles, maintenance A+R for up to 2 y (TN cohort responders), then oral A continuously until progressive disease (PD) or treatment discontinuation due to toxicity (both cohorts). The primary endpoint was safety. Secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR), all per Lugano. Results: Overall, 38 pts were enrolled (TN, n=18; R/R, n=20) with median age 66 y (range, 47–86). Baseline characteristics were (TN and R/R cohorts, respectively): stage IV disease in 88.9% and 95.0%, high-risk simplified MIPI score in 11.1% and 15.0%, bulky disease >5 cm in 16.7% and 30.0% or ≥10 cm in 5.6% and 10.0%, and blastoid morphology in 5.6% and 15.0%; R/R pts had a median of 2 prior lines of therapy. As of the data cutoff date (6/15/22), 6 (33.3%) TN pts and 4 (20.0%) R/R pts were receiving A monotherapy (Table). Most common any-grade AEs were nausea (n=14, 77.8%; TN) and neutropenia (n=11, 55.0%; R/R). Grade 3–4 AEs occurred in 13 (72.2%) TN pts and 17 (85.0%) R/R pts, most commonly neutropenia in both cohorts (n=7, 38.9% [TN]; n=10, 50.0% [R/R]). Serious AEs occurred in 11 (61.1%) TN pts and 13 (65.0%) R/R pts. There were no reports of ventricular tachyarrhythmia. Grade 3 atrial fibrillation occurred in 1 pt outside the safety reporting period and was not related to study treatment. Grade ≥3 major hemorrhage was reported in 2 (11.1%) TN pts and 3 (15.0%) R/R pts. Grade ≥3 hypertension was reported in 3 (16.7%) TN pts and 2 (10.0%) R/R pts. Five TN pts died (AE: pneumonitis, n=1; unknown, n=4) and 6 R/R pts died (AE: COVID and cerebrospinal meningitis, n=2; PD, n=2; unknown, n=2). ORR was 94.4% (n=17) in the TN cohort and 85.0% (n=17) in the R/R cohort, with CR rates of 77.8% (n=14) and 70.0% (n=14), respectively. Median DOR was not estimable (NE) in the TN cohort and 43.5 mo in the R/R cohort. Median PFS and overall survival were NE in the TN cohort (median follow-up 47.6 mo) and 28.6 mo and NE, respectively, in the R/R cohort (median follow-up 20.4 mo). Conclusions: Triple-combination ABR was tolerable and effective in pts with TN or R/R MCL. Clinical trial information: NCT02717624.