Poster: CLL-246 Venetoclax-Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia: 5-Year Results of the Randomized CLL14 Study

One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) has demonstrated significant improvement of progression-free survival (PFS) in the CLL14 trial. Long-term efficacy data including patients with high-risk disease are of particular interest.To provide updated efficacy and safety data.Randomized phase 3 study, patient enrollment 2015-2016, follow-up ≤9 years after last enrollment. The current median follow-up is 65.4 months.196 sites, 21 countries, including academic/community and ambulatory/hospital sites.Patients with treatment-naïve CLL and co-existing conditions (CIRS>6 and/or GFR <70 mL/min).A total of 432 patients were randomized 1:1 to 12 cycles (à28 days) of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab.The primary endpoint was PFS; secondary endpoints included safety, MRD, time to next treatment (TTNT), and overall survival (OS).PFS remained significantly superior for Ven-Obi compared to Clb-Obi (median not reached vs. 36.4 months; HR 0.35 [95%CI 0.26-0.46], P<0.0001). At 5 years after randomization, estimated PFS rate was 62.6% after Ven-Obi and 27.0% after Clb-Obi. TTNT was significantly longer after Ven-Obi (5-year TTNT 72.1% vs. 42.8%; HR 0.42, 95%CI 0.31-0.57, P<0.0001). Most next-line therapies were BTK inhibitors (54.3% Ven-Obi, 47.1% Clb-Obi). PFS and TTNT difference was maintained across all risk groups, including TP53mutation/deletion and unmutated IGHV status. Multivariable analysis indicated deletion17p and disease burden as independent prognostic factors for PFS in Ven-Obi-treated patients. Four years after treatment, 39 (18.1% of the intention-to-treat population) patients in the Ven-Obi arm still had uMRD (<10-4 by NGS in peripheral blood) compared to 4 (1.9%) uMRD in the Clb-Obi arm. Forty deaths were reported in the Ven-Obi arm (8 PD-related) and 57 in the Clb-Obi arm (23 PD-related); 5-year OS rate was 81.9% in the Ven-Obi and 77.0% in the Clb-Obi arm (HR 0.72 [0.48-1.09], P=0.12). No new safety signals were observed.Over 60% of Ven-Obi-treated patients have remained in remission 4 years after end of therapy, and the majority has not required 2nd-line CLL therapy. Hence, the 1-year fixed-duration Ven-Obi regimen continues to be an effective fixed-duration option for patients with CLL, also in the context of high-risk disease.