Acalabrutinib, venetoclax, and obinutuzumab (AVO) have emerged as a promising treatment option for patients with previously untreated chronic lymphocytic leukemia (CLL), particularly those with high-risk TP53 aberrations. A phase II study, recently published, evaluated the efficacy and safety of this fixed-duration combination therapy in a cohort enriched for high-risk CLL. The results suggest that AVO could become a new standard of care for this challenging patient population.
The study enrolled 72 treatment-naïve CLL patients, including 45 with TP53 aberrations, across multiple centers. The treatment regimen involved sequential introduction of acalabrutinib, obinutuzumab, and venetoclax, with treatment duration guided by measurable residual disease (MRD) assessment. Patients achieving undetectable MRD (uMRD) after 15 or 24 cycles were eligible to discontinue therapy. The primary endpoint was complete remission (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16.
Efficacy and Outcomes
The study demonstrated a CR rate with BM-uMRD of 42% at the start of cycle 16 in both the TP53-aberrant group and the overall cohort. The BM-uMRD rates were 71% and 78%, respectively. These findings are particularly significant given the historical challenges in treating CLL patients with TP53 aberrations, who often exhibit resistance to chemoimmunotherapy.
After a median follow-up of 55.2 months, 10 patients experienced disease progression, including four with transformation to a more aggressive lymphoma. Three patients died. The four-year progression-free survival (PFS) rates were 70% for patients with TP53 aberration and 96% for those without. The overall survival (OS) rates at four years were 88% and 100%, respectively.
Safety and Tolerability
The AVO regimen was generally well-tolerated. Hematologic toxicities were primarily low grade, and cardiovascular toxicities and bleeding complications were infrequent. This favorable safety profile is crucial, as many CLL patients are older and have comorbidities that can increase their risk of treatment-related complications.
Implications for CLL Treatment
The results of this phase II study suggest that AVO is a highly active and well-tolerated regimen for previously untreated high-risk CLL, including patients with TP53 aberrations. These findings support the use of AVO as a new standard-of-care treatment option, potentially offering improved outcomes compared to traditional chemoimmunotherapy approaches or continuous Bruton tyrosine kinase (BTK) inhibitor therapy. Further studies with longer follow-up are warranted to confirm these findings and to explore the optimal duration of therapy.
