VENETOCLAX‐OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 6‐YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY

Abstract

Background: One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). Due to its ongoing follow-up, the CLL14 study provides unique insights into long-term outcomes of pts after Ven-Obi therapy. Methods: Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to Ven-Obi or chlorambucil-obinutuzumab (Clb-Obi). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included safety, rates of minimal residual disease (MRD), time to next treatment (TTNT) and overall survival (OS). Results: Of 432 enrolled pts, 216 were randomly assigned to Ven-Obi, 216 to Clb-Obi. At a median follow-up of 76.4 months (interquartile range 52.5–80.5), PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs. 36.4 months; HR 0.40 [95% CI 0.31–0.52], p < 0.0001). Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatments, and in 141 cases in the Clb-Obi arm (with 103 second-line treatments). TTNT was significantly longer after Ven-Obi (6-year TTNT 65.2% vs. 37.1%; HR 0.44, 95% CI 0.33–0.58, p < 0.0001). In both arms, the most frequent second-line treatments were BTK inhibitors (61.5% in the Ven-Obi arm, 55.4% in the Clb-Obi arm). The PFS and TTNT difference between the two arms was maintained across all risk groups, including pts with TP53 mutation/deletion (median PFS 51.9 vs. 20.8 months; median TTNT 57.3 vs. 29.0 months) and unmutated IGHV status (median PFS 64.8 vs. 26.9 months; median TTNT 85.4 vs. 40.6 months). Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV and lymph node size ≥5 cm as independent negative prognostic factors for PFS in pts treated with Ven-Obi. Five years after treatment completion, 17 (7.9% of the intention-to-treat population) pts in the Ven-Obi arm still had uMRD (<10−4 by NGS in peripheral blood), 22 (10.2%) had low (L)-MRD (≥10-4 and <10-2) and 23 (10.6%) high (H)-MRD (≥10-2), compared to 4 (1.9%) uMRD, 9 (4.2%) L-MRD and 18 (8.3%) H-MRD in the Clb-Obi arm. Overall, 48 deaths were reported in the Ven-Obi arm (9 PD related) and 70 in the Clb-Obi arm (26 PD related); 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69 [0.48–1.01], p = 0.052). Second primary malignancies were reported in 30 pts in the Ven-Obi and 18 in the Clb-Obi arm; cumulative incidences 6 years after randomization were 14.2% and 8.5%, respectively (p = 0.071). No new safety signals were observed. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Roche, AbbVie Keywords: chronic lymphocytic leukemia (CLL), combination therapies Conflicts of interests pertinent to the abstract O. Al-Sawaf Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Research funding: AbbVie, BeiGene, Janssen, Roche Educational grants: AbbVie, AstraZeneca, Janssen, Gilead, Roche