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Obinutuzumab/Acalabrutinib/Venetoclax Combo Misses the Mark for MRD in Advanced Chronic Lymphocytic Leukemia (CLL)

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Bottom Line:

The combination of obinutuzumab (Gazyva), acalabrutinib (Calquence), and venetoclax (Venclexta) failed to meet the pre-specified rate of undetectable measurable or minimal residual disease (uMRD) following optimal debulking with bendamustine in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).


Forty-five adults with CLL underwent debulking with two cycles of bendamustine in the phase 2 CLL2-BAAG study. Patients then received induction and maintenance with obinutuzumab along with concurrent acalabrutinib and venetoclax. The primary endpoint was uMRD (<10-4) in peripheral blood at the end of induction treatment assessed centrally 12 weeks after the start of the last induction cycle. The median observation time was 13.8 months.


BTK inhibitors like acalabrutinib provide excellent long-term disease control in many patients with chronic lymphocytic leukemia. The BCL-2 inhibitor venetoclax offers the possibility, especially when combined with either antibody such as obinutuzumab, a humanized anti-CD20 monoclonal antibody, or a BTK inhibitor to achieve deep responses with undetectable measurable or minimal residual disease (uMRD), which allows for time-limited treatment. In addition, being able to stop therapy has significant potential benefits for patients.

The purpose of this study was to see if using the triplet using all three classes of agents could lead to higher rates of uMRD so that therapy could be stopped compared to that achieved by either of the venetoclax-based doublets.

  • Acalabrutinib is a BTK inhibitor similar to ibrutinib and zanubrutib
  • Obinutuzumab is a humanized anti-CD20 monoclonal antibody
  • Venetoclax is a BCL-2 inhibitor
  • Bendamustine is an alkylating agent, a type of chemotherapy.

Eligible patients:

  • Relapsed/refractory chronic lymphocytic leukemia requiring treatment according to the 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria
  • Aged 18 years or older
  • ECOG score 0-2 (ECOG 2) is defined as “capable of all self-care but unable to carry out any work activities. Up and about >50% of waking hours”. Those with lower scores are more capable.
  • 21 (47%) patients previously received a targeted agent.
  • 14 (32%) patients had del(17p13.1) or TP53 mutation


  • Thirty-four (71%) patients had uMRD in peripheral blood after six months of triple therapy, falling short of the pre-specified goal of 90% uMRD
  • At the February 25, 2021, data cutoff, 32 (71%) patients started maintenance therapy, and 9 (28%) were able to stop treatment
  • 8 patients (18%) had a complete response (CR) or CR with incomplete marrow recovery
  • 37 (82%) had a partial response
  • Median progression-free survival (PFS) and overall survival were not reached.
    • The estimated 12-month PFS rate was 94%.

Key Takeaways:

  • The use of this triple combination in routine practice cannot be recommended until such regimens show clear benefits over already well-studied venetoclax-based doublets in a clinical trial.
  • Previous data have shown that BTK inhibitors plus venetoclax are very effective in chronic lymphocytic leukemia, including but not limited to the GLOW, CAPTIVATE, and CLARITY trials.
  • Other trials had shown impressive results when obinutuzumab was added to venetoclax, such as CLL14.
  • Several other trials use similar triplets as used in this study, including BOVEN, which used venetoclax plus obinutuzumab and zanubrutinib (Brukinsa) to achieve 89% uMRD at ten months.


All combinations are not equal in their efficacy. Adding more treatment is not always the best course of action. It may only increase toxicity and will almost always be more immunosuppressive.

You can access the abstract in Lancet Oncology at Obinutuzumab, acalabrutinib, and venetoclax, after an optional debulking with bendamustine in relapsed or refractory chronic lymphocytic leukaemia (CLL2-BAAG): a multicentre, open-label, phase 2 trial.

Braxton Cole has more than 20 years of experience as a journalist, including over a decade covering hematology/oncology for various outlets.