A novel triplet therapy combining acalabrutinib, venetoclax, and obinutuzumab (AVO) has shown promising results in patients with chronic lymphocytic leukemia (CLL), particularly those with the high-risk TP53 aberration. The phase 2 trial, guided by measurable residual disease (MRD), demonstrated high rates of durable response and favorable outcomes for this challenging patient population. The findings, presented at the 66th American Society for Hematology (ASH) Annual Meeting and Exposition, and published in the Journal of Clinical Oncology, suggest a potential new standard of care for CLL.
The study evaluated the efficacy and safety of the AVO regimen in 72 patients, including 45 with TP53 aberrant CLL. This subgroup traditionally faces limited treatment options and poorer outcomes. The results showed that 42% of patients achieved complete remission with undetectable MRD in the bone marrow by the 16th treatment cycle, with equivalent results observed regardless of TP53 status. The overall response rate was 98.6%, with most patients experiencing lasting remissions after completing therapy.
Durable Remission and Safety Profile
The time-limited AVO regimen provided durable remission in patients with TP53 aberrations, with four-year progression-free survival and overall survival rates of 70% and 88%, respectively. Importantly, the treatment was well-tolerated, with low rates of cardiovascular toxicity and bleeding complications.
According to Matthew Davids, MD, MMSC, Clinical Research Director in the Division of Lymphoma at Dana-Farber, the AVO triplet was well-tolerated for most patients, suggesting that the regimen can be considered as an option even in older patients and those with co-morbidities who desire a highly effective time-limited treatment with the potential to achieve deep responses leading to durable remissions after completing therapy.
Implications for CLL Treatment
This study fills a gap in the data from the AVO arm of the phase 3 AMPLIFY trial, which focused exclusively on patients without TP53 aberrations. The current findings extend the applicability of the AVO regimen to patients with high-risk TP53 aberrations, a group that typically experiences shorter remissions after currently approved time-limited targeted therapies for CLL. The durable remissions observed with AVO, coupled with the favorable safety profile, suggest that this regimen represents a promising new treatment option for this challenging patient population. These findings lay the groundwork for future randomized trials to further evaluate the potential of AVO relative to other approved regimens for this population.
"Our data in patients with CLL with high-risk TP53 aberration complement the data in the AVO arm of the phase 3 AMPLIFY study in patients with standard-risk CLL and suggest that this regimen can be considered as a new standard of care option for a broad population of patients with CLL," said Davids.
