Ibrutinib monotherapy has shown poor outcomes in patients with chronic lymphocytic leukemia (CLL) with 11q deletion or TP53 mutation or deletion (O’Brien. ASH 2016). Ublituximab is a novel monoclonal antibody that targets a unique epitope on the B-lymphocyte CD20 antigen. GENUINE is the first randomized phase 3 trial conducted to assess the addition of a novel agent to ibrutinib in high-risk, relapsed/refractory (RR) CLL.
Eligible patients were ibrutinib-naïve with del17p, del11q, and/or a TP53 mutation. They were randomized to receive ibrutinib 420 mg once daily alone or with ublituximab, dosed 900 mg on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6, and every 3 cycles thereafter. The primary end point was overall response rate (ORR); secondary end points included complete response (CR) rate, minimal residual disease (MRD) negativity, progression-free survival (PFS), and safety.
A total of 126 patients were randomized; 9 were excluded prior to treatment. Of the 117 patients treated, 59 received ublituximab and ibrutinib, and 58 received ibrutinib monotherapy. High-risk cytogenetics were well-balanced, median age was 67 years, patients had received a median of 3 prior therapies, and more than 70% were male. At 12-month follow-up, ORR per independent central review was 78% for the ublituximab and ibrutinib arm versus 45% for ibrutinib alone (P <0.001). The combination of ublituximab and ibrutinib had a CR rate of 7% versus 0% for ibrutinib alone, and an MRD-negativity rate of 19% versus 2%, respectively (P <0.01). The study also showed a trend in improvement of PFS with the combination but it was not statistically significant at the time of the analysis, and the study is no longer powered to detect such a change.
Overall, treatment was well-tolerated by both groups. In the ublituximab and ibrutinib arm, infusion reactions were the most prevalent adverse event (54%, grade 3/4: 5%). In examining the key laboratory abnormalities, there was an increased incidence of neutropenia in the ublituximab and ibrutinib arm (22% vs 12% with ibrutinib alone); however, the rates of grade 3/4 neutropenia were similar between the 2 arms, and other laboratory abnormalities were similar.
The researchers concluded that the addition of ublituximab to ibrutinib demonstrated a superior response rate compared with ibrutinib alone, without additional clinically significant toxicity. This combination represents a promising investigational target for patients with high-risk, RR CLL.
Sharman JP, et al. ASCO Abstract 7504.