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7504 Background: Patients (pts) with high-risk chronic lymphocytic leukemia (CLL) defined by interruptions in TP53 (either by mutation or deletion) or loss of chromosome 11q experience inferior outcomes with ibrutinib (IB) monotherapy (O’Brien ASH 2016). Ublituximab (UTX) is a novel glycoengineered mAb with enhanced ADCC targeting a unique epitope on the CD20 antigen. GENUINE is the first randomized Ph 3 trial conducted assessing the addition of a novel agent to ibrutinib in high-risk rel/ref CLL, and evaluates IB monotherapy vs. UTX + IB. Methods: Eligible pts with rel/ref CLL and centrally confirmed del17p, del11q, and/or a TP53 mutation were randomized 1:1 to receive IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cycle 1, D1 of Cycle 2-6, and Q3 Cycles thereafter). There was no limit on number of prior therapies. Prior IB exposure was excluded. The primary endpoint was overall response rate (ORR) per iwCLL 2008 criteria, with secondary endpoints including CR rate, MRD negativity, PFS, time to response (TTR) and safety. Results: 126 pts were randomized at sites in the US and Israel, with 117 pts treated (59 on UTX + IB, 58 on IB alone). Median age 67, median 3 prior therapies (range 1-8), > 70% of were male. High-risk cytogenetics were relatively balanced with ~ 50% of pts having del17p. UTX+IB was well tolerated, with infusion reactions the most prevalent AE (44%, GR3/4 5%). Neutropenia was comparable with the combination (17%, Gr3/4 7% vs. 10%, Gr3/4 9%), and other AE’s were similar or lower with UTX+IB vs. IB alone (all grades), including fatigue (17% vs. 31%), dizziness (12% vs. 21%), contusion (12% vs. 26%), anemia (10% vs. 16%), and myalgia (9% vs. 14%). At median follow-up of 12 mo, best ORR per independent central review was 80% for UTX + IB vs. 47% for IB alone (p < 0.001). While not powered for secondary endpoints, observed advantages were seen in PFS and radiographic CR rate in the UTX + IB arm. CR and MRD confirmation is ongoing. Median TTR for the combo was 1.97 mo vs. 3.8 mo for IB alone. Both arms have responses pending confirmatory assessments. Conclusions: The addition of UTX to IB demonstrated a superior response rate compared to IB alone without additional clinically significant toxicity. Clinical trial information: NCT02301156.