Acalabrutinib, venetoclax, and obinutuzumab (AVO) demonstrate promising results as a frontline treatment for chronic lymphocytic leukemia (CLL), particularly in high-risk patients. Updated data from a phase 2 trial (NCT03580928) showed a high rate of bone marrow undetectable minimal residual disease (BM-uMRD) and a favorable safety profile, suggesting the potential for a new standard of care.
The study, an investigator-initiated phase 2 trial, enrolled 44 previously untreated CLL patients, with a significant proportion (39%) harboring TP53 aberrations. The AVO regimen consisted of acalabrutinib (100 mg bid), obinutuzumab (standard dosing), and venetoclax (4-week ramp-up to 400 mg qd). The primary endpoint was the rate of BM-uMRD complete response (CR) at cycle 16 day 1 (C16D1).
High Efficacy and Deep Remissions
After a median follow-up of 19 months, the overall response rate was 100%, with 43% achieving CR/CRi and 57% achieving partial response (PR). Notably, 78% of patients achieved BM-uMRD at C16. In the subgroup of patients with TP53-aberrant disease, 70% achieved BM-uMRD. "The AVO triplet is highly active, with 78% achieving BM-uMRD after 15 months of time-limited therapy in a frontline CLL population that included nearly 40% pts with TP53 aberrant disease," the researchers noted.
Favorable Safety Profile
The AVO regimen was generally well-tolerated. Common non-hematologic adverse events (AEs) included headache (80%), fatigue (77%), and bruising (57%), mostly grade 1 or 2. Grade 3/4 hematologic toxicities included neutropenia (34%), thrombocytopenia (23%), and anemia (4.5%). Importantly, there was a low rate of ≥Grade 3 infection (2%) and atrial fibrillation (2%), and no cases of major bleeding or febrile neutropenia. Transient lab TLS occurred in 2 patients (4.5%) just after starting obinutuzumab, prior to venetoclax initiation. The use of a 4-week ramp-up for venetoclax appeared to mitigate the risk of TLS.
Implications for CLL Treatment
These results support the ongoing phase 3 trial (CL-311, NCT03836261) evaluating AVO in a larger cohort of CLL patients. The AVO triplet has the potential to become a new standard frontline therapy option for CLL patients, particularly those with high-risk disease. The time-limited nature of the therapy and the potential for deep remissions, as indicated by the high BM-uMRD rate, are particularly appealing. The favorable safety profile further supports its potential as a well-tolerated and effective treatment option.
