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Venetoclax Combined with Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia

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Authored by Dr. Brian Koffman

The Bottom Line:

Five years after completing venetoclaxobinutuzumab to treat chronic lymphocytic leukemia (CLL), over half of the treatment-naive patients remained in remission, and over 60% did not require second-line treatment, including many high-risk patients.

Who Performed the Research and Where Was it Presented:

Dr. Othman Al-Sawa led an international group presenting the six-year follow-up results of the CLL14 Study at the European Hematology Association (EHA) Annual Congress in Frankfurt in 2023. The German CLL Study group has done many large, lengthy, and important trials that have changed our fundamental understanding of how to best care for CLL, and the CLL14 trial is one of them.


One-year fixed-duration venetoclax – obinutuzumab (Ven-Obi) is now an established standard treatment for patients with treatment-naive CLL. One of the reasons it is part of the standard of care is that the CLL14 study previously demonstrated high efficacy and good tolerability of Ven-Obi in patients with CLL and coexisting conditions. The study is still ongoing and provides an excellent opportunity to study the outcomes of patients long after Ven-Obi treatment completion.

Methods and Participants:

The aim of this report is to provide updated efficacy and safety data from the ongoing follow-up of the CLL14 study, with all patients having been off-study treatment for over 5 years. Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to 12 cycles of venetoclax with six cycles of obinutuzumab or 12 cycles of chlorambucil with six cycles of obinutuzumab (Clb-Obi). Today using a comparator of chlorambucil with six cycles of obinutuzumab (Clb-Obi) would no longer be ethical because this and other research have proven the superiority of venetoclax – obinutuzumab over chlorambucil with obinutuzumab (Clb-Obi). The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, rates of minimal (or measurable) residual disease (MRD), time to next treatment (TTNT), and overall survival (OS). Follow-up is ongoing.


  • Of the 432 enrolled patients, 216 were randomly assigned to the Ven-Obi cohort and 216 to receive Clb-Obi.
  • The median follow-up was 76.4 months.
  • PFS remained superior, more than double for Ven-Obi compared to Clb-Obi (median 76.2 vs 36.4 months).
  • Six years after randomization, the estimated PFS rate was 53.1% after Ven-Obi and 21.7% after Clb-Obi.
  • Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatment initiations and in 141 cases in the Clb-Obi arm (with 103 second-line treatments).
  • TTNT was also statistically and clinically significantly longer after Ven-Obi (6-year TTNT 65.2% vs. 37.1%;).
  • The most frequent second-line treatments in both arms 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 not surprisingly maintained across all risk groups, including patients.
    • with P53 mutation/deletion (median PFS 51.9 vs 20.8 months; median TTNT 57.3 vs 29.0 months)
    • 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 patients treated with Ven-Obi.
  • Five years after treatment completion, 17 (7.9% of patients in the Ven-Obi arm still had undetectable measurable (minimal) residual disease (uMRD) (<10-4 by next-generation sequencing (NGS) in peripheral blood).
  • 48 deaths were reported in the Ven-Obi arm, of which 9 were progressive disease (PD) related and 70 in the Clb-Obi arm (26 PD related).
  • At six years, the overall survival (OS) rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm.
  • Second primary malignancies (SPM) were found in 30 patients who had taken Ven-Obi and 18 who had had the Clb-Obi; cumulative incidences of second cancers six years after randomization were 14.2% and 8.5%.
  • Two Richter transformations were reported in the Ven-Obi arm and 4 in the Clb-Obi arm.
  • No new safety signals were discovered.


These are exciting results. These data confirm a long-term progression-free survival benefit of fixed-duration Ven-Obi treatment compared to Clb-Obi, including all patients with high-risk CLL. Five years after completing Ven-Obi, over half of the patients remained in remission, and over 60% had not required second-line treatment. Reaching uMRD improved outcomes, and TP53 deletion/mutation, unmutated IGHV, and lymph node size ≥5 cm decreased your chances of not progressing.

In summary, a one-year Ven-Obi regimen is an effective fixed-duration option for patients with CLL and coexisting conditions who can often enjoy a long period of disease control after a one-year fixed duration of therapy.

That said, it is not a curative therapy, with less than 8% of patients having undetectable disease five years after completion of therapy.

Links and Resources:

Watch Dr. Brian Koffman’s monologue on the abstract:

Venetoclax Combined with Obinutuzumab for Previously Untreated CLL


Stay strong. We are all in this together.

Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.