The triplet regimen of acalabrutinib, venetoclax, and obinutuzumab (AVO) continues to show durable responses in the frontline treatment of chronic lymphocytic leukemia (CLL), according to findings from a phase 2 trial (NCT03580928). The study, presented by Catherine C. Coombs, MD, at the Oncology Town Hall meeting, revealed a progression-free survival (PFS) rate of 93% at a median follow-up of 35 months, indicating a significant advancement in CLL therapy. However, the study also highlighted that patients with TP53-aberrant disease did not respond well, representing a continuing unmet need.
Efficacy and Response Rates
The trial enrolled treatment-naïve patients with CLL, including an all-comers portion (n = 37) and a multicenter expansion focused on patients with TP53-aberrant disease (n = 31). The AVO regimen involved initial treatment with acalabrutinib, followed by the addition of obinutuzumab and then venetoclax. The primary endpoint was the rate of achievement of undetectable minimal residual disease (uMRD) complete response (CR).
The overall response rate among all patients was 98%, with 48% achieving a CR and 50% achieving a partial response (PR). Notably, the CR rates were similar between patients with TP53-wild type disease (44%) and those with TP53-aberrant disease (52%). High rates of uMRD were observed in both peripheral blood (86%) and bone marrow (86%) across all patients, regardless of TP53 status.
Safety and Tolerability
The most common adverse events (grades 1-3) included headache (78%), fatigue (76%), and bruising (66%). Hematologic toxicities, such as neutropenia (37% grade 3/4), thrombocytopenia, and anemia, were also observed but did not frequently lead to treatment discontinuations. Grade 3 non-COVID-19 infections occurred in 5.8% of patients, and 9% experienced COVID-19 infections. Dose reductions were required in 21% of patients, with acalabrutinib and venetoclax being the most common drugs requiring adjustment.
Treatment Discontinuation and Outcomes
Forty-three patients who achieved bone marrow uMRD discontinued treatment, with a median time off therapy of 18.8 months (range, 0-30.4). Four patients experienced disease recurrence after discontinuation. Over the follow-up period, there were 4 progression events and 1 death due to COVID-19 pneumonia. The study reported that 92.6% of all patients were progression-free and alive, and 98.5% were alive at a median follow-up of 35 months.
Implications for CLL Treatment
These findings suggest that the AVO triplet regimen is a highly effective and well-tolerated frontline treatment option for CLL. The high rates of uMRD and durable responses observed in the trial support the potential for treatment discontinuation in patients who achieve deep remissions. However, the limited response in patients with TP53-aberrant disease underscores the need for further research and development of targeted therapies for this high-risk subgroup.
