VENETOCLAX‐OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 6‐YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY
Othman Al‐Sawaf, Sandra Robrecht, C. Zhang, Stefano Olivieri, Y. M. Chang, Anna‐Maria Fink, Eugen Tausch, C. Schneider, Matthias Ritgen, K.-A. Kreuzer, Liliya Sivcheva, Carsten Utoft Niemann, Anthony P. Schwarer, Javier Loscertales, Robert Weinkove, Dirk Strumberg, Allanah R. Kilfoyle, Eva Diana Runkel, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer
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