According to a longitudinal analysis of minimal residual disease (MRD) dynamics in the CLL14 study, appearance of detectable MRD was significantly slower after fixed-duration treatment with venetoclax and obinutuzumab (Ven-Obi) than chlorambucil and obinutuzumab (Clb-Obi) therapy in patients with previously untreated chronic lymphocytic leukemia (CLL). Progression-free survival (PFS) and undetectable MRD rates remained superior in the Ven-Obi arm compared with the those in the Clb-Obi arm. The findings were published in the Journal of Clinical Oncology.
The CLL14 study is an ongoing phase 3, open-label, randomized study of Ven-Obi compared with Clb-Obi in patients with previously untreated CLL and coexisting conditions (ClinicalTrials.gov Identifier: NCT02242942). The study investigators previously demonstrated that a fixed-treatment duration of 12 cycles of Ven-Obi therapy yielded significantly higher rates of undetectable MRD and longer PFS than Clb-Obi therapy in patients with previously untreated CLL and coexisting conditions.
“With all patients off treatment for at least three years, we report a detailed analysis of [MRD] kinetics and long-term outcome of patients treated in the CLL14 study,” the authors wrote.
In the CLL14 study, 432 patients were randomly assigned to receive 6 cycles of obinutuzumab with 12 cycles of venetoclax (n=216) or chlorambucil (n=216). The primary endpoint was PFS. Key secondary end points included rates of undetectable MRD and overall survival (OS). For the analysis of MRD kinetics, the researchers developed a population-based growth model.
At 3 months after treatment completion, 40% of patients in the Ven-Obi arm and 7% of patients in the Clb-Obi arm had undetectable MRD levels (<10-6 by next-generation sequencing) in peripheral blood. The median MRD doubling time following treatment was longer in patients who were treated with Ven-Obi than those treated with Clb-Obi (median, 80 vs 69 days; P =.0039). The median time to MRD conversion in patients with MRD levels <10-4 at the end of treatment to MRD levels ≥10-4 (by next-generation sequencing) was 21.0 months in those treated with Ven-Obi and 6.0 months in those treated with Clb-Obi.
In both treatment groups, patients who had had undetectable MRD in peripheral blood and detectable MRD in bone marrow (≥10-4) had shorter MRD doubling time than those who had had undetectable MRD in both peripheral blood and bone marrow at 3 months after treatment (median, 60 vs 80 days in the Ven-Obi arm and 42 vs 52 days in the Clb-Obi arm).
At a median follow-up duration of 52.4 months, PFS remained superior among patients in the Ven-Obi arm compared with those in the Clb-Obi arm (median, not reached vs 36.4 months; hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.45; P <.0001). The estimated 4-year PFS rate was 74.0% among patients treated with Ven-Obi and 35.4% among those treated with Clb-Obi. No difference in OS was observed between the treatment arms (HR, 0.85; 95% CI, 0.54–1.35; P =.49).
No new treatment-related adverse events were observed with this analysis.
“These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission,” the authors wrote. “The MRD analyses indicate a deep clearance of residual disease across compartments by Ven-Obi compared with Clb-Obi. Longer follow-up and further randomized studies are warranted to compare this regimen with other frontline treatment strategies.”
Disclosure: This research was supported by Hoffmann-La Roche Ltd and AbbVie Inc. Please see the original reference for a full list of disclosures.
Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. Published online October 28, 2021. J Clin Oncol. 2021;JCO2101181. doi:10.1200/JCO.21.01181