Phase III Study Evaluates Frontline Doublets in CLL

By Cecilia Brown - Last Updated: May 19, 2023

Data from a phase III study “indicate sustained long-term efficacy” of fixed-duration venetoclax plus obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia (CLL).

Othman Al-Sawaf, MD, of University of Cologne, University College London, and the Francis Crick Institute in London, and colleagues conducted the research and published their findings in Nature Communications.

They conducted the research to address the “limited” data on “long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax” in patients with CLL.

Dr. Al-Sawaf and colleagues included 432 patients with previously untreated CLL in the open-label, parallel-group study. They randomized patients 1:1 to receive one year of venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). The study’s primary endpoint was investigator-assessed progression-free survival (PFS). Its secondary endpoints included measurable residual disease (MRD) and overall survival.

With a median follow-up of 65.4 months, the PFS was “significantly superior” in patients who received venetoclax plus obinutuzumab compared with those who received chlorambucil plus obinutuzumab (hazard ratio [HR], 0.35; 95% CI, 0.26-0.46; P<.0001), the study’s authors wrote. The estimated PFS rate five years after randomization was 62.6% in patients who received venetoclax plus obinutuzumab, while it was 27% in those who received chlorambucil plus obinutuzumab.

“In both arms, MRD status at the end of therapy is associated with longer PFS,” Dr. Al-Sawaf and colleagues wrote.

MRD-positive status was associated with increased expression of ABCB1, whereas MRD-negative status was associated with BCL2L11 expression. Inflammatory response pathways were “enriched” in patients with an MRD-positive status, but solely in the group receiving venetoclax plus obinutuzumab, according to the study’s authors.

“These data indicate sustained long-term efficacy of fixed-duration [venetoclax plus obinutuzumab] in patients with previously untreated CLL,” Dr. Al-Sawaf and colleagues concluded. “The distinct transcriptomic profile of MRD-positive status suggests possible biological vulnerabilities.”


Al-Sawaf O, Zhang C, Jin HY, et al. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023;14(1):2147. doi:10.1038/s41467-023-37648-w

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