KEY TAKEAWAYS
- The phase 3 study compared the efficacy and safety of venetoclax-obinutuzumab (Ven-Obi) versus chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL and coexisting conditions.
- Investigator-assessed PFS was the primary endpoint. The secondary objectives were safety, MRD, TTNT, and OS.
- The study confirmed the long-term PFS benefits of the 1-year Ven-Obi treatment over Clb-Obi, including for high-risk CLL patients.
The CLL study included patients (pts) who had not administered prior treatment for chronic lymphocytic leukemia (CLL) and had concurrent medical conditions who received venetoclax-obinutuzumab (Ven-Obi) or chlorambucil-obinutuzumab (Clb-Obi) in a 1:1 ratio. The study’s primary objective was to evaluate progression-free survival (PFS) as assessed by the investigators. Secondary objectives encompassed assessing safety, rates of minimal residual disease (MRD), the duration until the subsequent treatment (TTNT), and overall survival (OS).
Among the 432 pts enrolled, 216 were randomly assigned to the Ven-Obi, and 216 were allocated to the Clb-Obi group. After a median follow-up of 76.4 mos (interquartile range of 52.5–80.5), the study demonstrated that Ven-Obi consistently outperformed Clb-Obi in terms of PFS(median 76.2 vs. 36.4 mos; HR 0.40 [95% CI 0.31–0.52], p < 0.0001). Progressive disease (PD) was observed in 67 cases in Ven-Obi cohort, with 39 individuals receiving second-line treatments, and 141 cases in the Clb-Obi group (103 second-line treatments). Additionally, TTNT was significantly prolonged following treatment with Ven-Obi, with a 6-year TTNT of 65.2% compared to 37.1% for Clb-Obi (HR 0.44, 95% CI 0.33–0.58, p < 0.0001). The most frequently administered second-line treatments in both treatment arms consisted of BTK inhibitors, accounting for 61.5% in the Ven-Obi group and 55.4% in the Clb-Obi group.
The disparity in PFS and TTNT between the two treatment arms remained consistent across all risk categories, including pts with TP53 mutation/deletion (median PFS 51.9 vs. 20.8 months; median TTNT 57.3 vs. 29.0 mos) and those with unmutated IGHV status (median PFS 64.8 vs. 26.9 mos; median TTNT 85.4 vs. 40.6 mos). A multivariate analysis determined that TP53 deletion/mutation, unmutated IGHV status, and lymph node size ≥5 cm independently constituted adverse prognostic factors for PFS in patients treated with Ven-Obi.
Five years after the completion of treatment,17 pts in the Ven-Obi group (7.9% of the intention-to-treat population) exhibited uMRD(<10-4 by NGS in peripheral blood), while 22 pts (10.2%) had low-level MRD (L-MRD,≥10-4 and <10-2), and 23 pts (10.6%) had high-level MRD (H-MRD,≥10-2). In comparison, the Clb-Obi group had four pts (1.9%) with uMRD, nine pts (4.2%) with L-MRD, and 18 pts (8.3%) with H-MRD.
Forty-eight deaths were reported in the Ven-Obi group, of which nine were related to PD. In the Clb-Obi group, there were 70 deaths, with 26 attributed to PD. The 6-year OS rate was 78.7% in the Ven-Obi group and 69.2% in the Clb-Obi group (HR 0.69 [0.48–1.01], p = 0.052).
Second primary malignancies were registered in 30 pts in the Ven-Obi group and 18 in the Clb-Obi group, with cumulative incidences at six years after randomization of 14.2% and 8.5%, respectively (p = 0.071). No new safety signals were reported in the study.
The data provides evidence of the sustained PFS advantage associated with the fixed-duration Ven-Obi treatment compared to Clb-Obi, even for pts with high-risk CLL. Five years after completing the Ven-Obi regimen, over half of the patients maintained their remission status, and over 60% did not necessitate a second-line treatment. The one-year Ven-Obi regimen emerges as a highly effective and viable fixed-duration treatment option for pts with CLL alongside concurrent medical conditions.
Source: https://onlinelibrary.wiley.com/doi/10.1002/hon.3163_25
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02242942
Al-Sawaf, O., Robrecht, S., Zhang, C., Olivieri, S., Chang, Y.M., Fink, A.M., Tausch, E., Schneider, C., Ritgen, M., Kreuzer, K., Sivcheva, L., Niemann, C., Schwarer, A., Loscertales, J., Weinkove, R., Strumberg, D., Kilfoyle, A., Runkel, E.D., Eichhorst, B., Stilgenbauer, S., Jiang, Y., Hallek, M. and Fischer, K. (2023), VENETOCLAX-OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 6-YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY. Hematological Oncology, 41: 58-60. https://doi.org/10.1002/hon.3163_25
