Ublituximab and Ibrutinib for Previously Treated, Genetically High-Risk CLL: Results of the GENUINE Phase 3 Study

Conference Correspondent - ASCO 2017 - Chronic Lymphocytic Leukemia, Conference Correspondent

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.

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