Adding acalabrutinib to treatment with obinutuzumab and venetoclax may not provide a clinical benefit in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to research published in The Lancet Haematology.1

The triplet, given after optional debulking with bendamustine, produced a 100% response rate in the phase 2 CLL2-BAAG trial. However, the rate of undetectable minimal residual disease (uMRD) did not meet the prespecified activity threshold.

The uMRD rate was 76%, which is lower than the 83% uMRD rate seen with obinutuzumab and venetoclax in the previous CLL2-BAG trial.2 

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The current trial ( Identifier: NCT03787264) included 45 patients with relapsed or refractory CLL. At baseline, the patients’ median age was 60 years, and 29% were women. Patients had received a median of 1 prior therapies, the most common of which was combination fludarabine, cyclophosphamide, and rituximab. Patients had low-risk (7%), intermediate-risk (37%), high-risk (30%), or very high-risk (26%) disease.

Patients with a higher tumor load could undergo debulking with 2 cycles of bendamustine (70 mg/m² IV on days 1 and 2 repeated after 28 days). This was followed by 6 cycles of induction with obinutuzumab (1000 mg IV on days 1, 2, 8, and 15 of the first cycle and every 4 weeks in cycles 2 to 6). Twice daily acalabrutinib (100 mg orally) was added in the second cycle. Venetoclax was added in the third cycle (with a weekly dose ramp up from 20 mg to 400 mg orally over 5 weeks). 

For maintenance, acalabrutinib and venetoclax treatment remained the same, but obinutuzumab (1000 mg) was given every 3 months for up to 24 months or until patients achieved a complete response and uMRD in peripheral blood for 2 assessments with an interval of 3 months.

At the end of induction, 100% of patients had a response to treatment. Most (82%) were partial responses, but 18% of patients achieved a complete response or complete response with incomplete recovery of bone marrow. 

The prespecified threshold for uMRD was 90%, but only 76% of patients achieved uMRD at the end of induction. 

“Although the primary endpoint of the trial was not met, the activity and the uMRD rate are at least in the same range or maybe higher than with other established regimens,” the researchers wrote. 

The most common grade 3-4 adverse events in this trial, observed during induction and maintenance, were thrombocytopenia (27%), neutropenia (27%), tumor lysis syndrome (11%), infections (11%), infusion reactions (9%), and anemia (9%).

Over a median observation time of 13.8 months, 2 patients experienced Richter transformation. 

Disclosures: This research was supported by Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


  1. Cramer P, Fürstenau M, Robrecht S, et al. 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. Lancet Haematol. Published online August 18, 2022. doi:10.1016/S2352-3026(22)00211-3
  2. Cramer P, von Tresckow J, Bahlo J, et al. Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): Primary endpoint analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(9):1215-1228. doi:10.1016/S1470-2045(18)30414-5