Frontline triplet therapy with acalabrutinib, venetoclax, and obinutuzumab for chronic lymphocytic leukemia (CLL) is well-tolerated and highly active, warranting further study, according to phase 2 results published in The Lancet Oncology.

The open-label, single-arm study included 37 patients with CLL and aimed to determine whether the triplet therapy would induce deep and durable remissions.

Based on prior studies evaluating BTK and BCL-2 inhibitors in CLL, the authors hypothesized that combining the BTK inhibitor acalabrutinib with the BCL-2 inhibitor venetoclax and the anti-CD20 antibody obinutuzumab in a time-limited regimen guided by minimal residual disease (MRD) would lead to deep remissions.

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The authors used a 4-week venetoclax dose ramp-up to debulk tumors. There was no observed tumor lysis syndrome with this approach.

A total of 36 patients continued the study drugs for at least 15 cycles. There were 12 who discontinued acalabrutinib and venetoclax after complete remission with undetectable MRD after 15 cycles. A total of 19 patients discontinued the study drugs after undetectable MRD in peripheral blood after 24 cycles. There were 4 patients who remained on the study drugs as of data cutoff.

Median follow up was 27.6 months, and all patients were alive at follow-up. The primary endpoint was not met, as only 38% of patients achieved complete remission by the start of cycle 16.

No patients who achieved complete remission had disease recurrence as of data cutoff.

All patients had at least 1 adverse event, but no treatment-related deaths occurred. A total of 43% of patients had grade 3 or 4 neutropenia. 

Patients achieved complete remission and undetectable MRD at similar rates regardless of their TP53 or IGHV mutation status.

In this study, patients who had both an International Workshop on Chronic Lymphocytic Leukaemia (iwCLL) criteria-defined complete remission and undetectable MRD in bone marrow were able to discontinue treatment at the start of cycle 16. 38% of patients met this endpoint. Patients who did not meet the criterion were able to continue therapy for an additional 9 cycles.

The authors observed no progression at a median of 7.6 months off therapy.

Further long-term study is needed to determine response duration and whether patients respond a second time if the disease progresses. Future studies also need to evaluate whether obinutuzumab enhances efficacy compared to doublet therapy.

Overall, the authors found that triplet therapy with acalabrutinib, venetoclax, and obinutuzumab is an option for previously untreated patients with CLL. It has a favorable safety profile, and the triplet therapy is being studied in a phase 3 trial.

Disclosure: This research was supported by AstraZeneca. Please see the original reference for a full list of disclosures.


Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;S1470-2045(21)00455-1. doi:10.1016/S1470-2045(21)00455-1