Measurable Residual Disease Dynamics and Extended Follow-up in CLL14 Trial of Venetoclax/Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia

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In an analysis of the pivotal CLL14 trial reported in the Journal of Clinical Oncology, Al-Sawaf et al found that venetoclax plus obinutuzumab was associated with higher rates of undetectable measurable residual disease (MRD) and prolonged MRD doubling time vs chlorambucil plus obinutuzumab at 3 months after study treatment was stopped. A progression-free survival benefit was maintained with venetoclax/obinutuzumab in extended follow-up.

The CLL14 trial supported the May 2019 approval of venetoclax in combination with obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma on the basis of improved progression-free survival.

In the trial, 432 patients were randomly assigned to receive 6 cycles of obinutuzumab plus either 12 cycles of venetoclax (n = 216) or 12 cycles of chlorambucil (n = 216) in 28-day cycles. At the time of the current analysis, all patients had been off study treatment for more than 3 years.

Key Findings

At 3 months after treatment, undetectable MRD at 106 on next-generation sequencing in peripheral blood was observed in 39.8% of the venetoclax/obinutuzumab group vs 6.5% of the chlorambucil/obinutuzumab group. Median MRD doubling time was 80 days after venetoclax/obinutuzumab vs 69 days after chlorambucil/obinutuzumab (P =.0039).

Among patients with available data at month 30, MRD at < 104 was found in 26.9% vs 3.2% of patients (P < .0001). Median time to MRD conversion, defined as an increase from MRD < 104 at the end of treatment to MRD ≥ 104, was 21.0 months vs 6.0 months (P < .0001).

At a median follow-up of 52.4 months, median progression-free survival was not reached vs 36.4 months (hazard ratio [HR] = 0.33, 95% confidence interval [CI] =  0.25–0.45, P < .0001), with an estimated 4-year rate of 74.0% vs 35.4%.

Next-line antileukemic treatment was received by 17 patients in the venetoclax/obinutuzumab group vs 70 in the chlorambucil/obinutuzumab group, with the time to next treatment being significantly longer with venetoclax/obinutuzumab (HR = 0.46, 95% CI = 0.32–0.65, P < .0001). Among patients receiving subsequent treatment, monotherapy with a Bruton’s tyrosine kinase inhibitor was used in 47% vs 50% of patients.

At the time of analysis, death had occurred in 15.7% vs 19.0% of patients (overall survival HR = 0.85, 95% CI = 0.54–1.35, P = .49). Estimated 4-year overall survival was 85.4% vs 83.1%. At 3 years after the end of treatment, overall survival was 92.2% and 94.6% among patients with undetectable MRD at the end of treatment compared with 72.7% and 82.7% in those with detectable MRD.

The investigators concluded: “Appearance of MRD after [venetoclax/obinutuzumab] is significantly slower than that after [chlorambucil/obinutuzumab], with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of [venetoclax/obinutuzumab]-treated patients remaining in remission.”

Kirsten Fischer, MD, of the University Hospital of Cologne, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Deutsche Forschungsgemeinschaft and by F. Hoffmann-La Roche and AbbVie. For full disclosures of the study authors, visit

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