Acalabrutinib, venetoclax, and obinutuzumab, when used in combination, show promise as a frontline treatment for chronic lymphocytic leukemia (CLL), offering a chemotherapy-free, time-limited approach. This regimen aims to provide deep remissions with good tolerability across a broad spectrum of previously untreated CLL patients, including those with high-risk disease.
Rationale for the Triplet Combination
The combination of BTK and BCL-2 inhibitors has shown synergistic effects in preclinical studies of CLL. While the combination of ibrutinib (a first-generation BTK inhibitor) and venetoclax can achieve deep responses, the broad range of kinases inhibited by ibrutinib can lead to toxicities such as atrial fibrillation, infection, neutropenia, and hypertension. Acalabrutinib, a more specific, second-generation BTK inhibitor, has demonstrated a similar efficacy profile but with improved tolerability compared to ibrutinib. Unlike ibrutinib, acalabrutinib does not alter venetoclax exposure, suggesting that the combination may achieve deep responses with fewer toxicities.
The ELEVATE-TN study suggests that adding obinutuzumab to acalabrutinib may improve progression-free survival compared to acalabrutinib alone, without a substantial increase in toxicity. The hypothesis is that combining acalabrutinib with venetoclax and obinutuzumab in an MRD-guided, time-limited regimen would lead to deep remissions with good tolerability for a broad population of patients with previously untreated chronic lymphocytic leukaemia, including those with higher-risk disease.
Study Design and Objectives
This phase 2, investigator-sponsored trial evaluated the activity and safety of acalabrutinib, venetoclax, and obinutuzumab in patients with frontline CLL. The study also explored the feasibility of a shorter, more convenient 4-week venetoclax dose ramp-up, rather than the traditional 5-week ramp-up, through initial tumour debulking with a 3-month acalabrutinib plus obinutuzumab lead-in.
Key Findings and Clinical Implications
Despite not meeting the primary endpoint, the study demonstrated a high level of activity and a favorable tolerability profile for the acalabrutinib, venetoclax, and obinutuzumab regimen. This suggests that the triplet therapy should be further explored as a valuable new therapeutic option for a broad population of previously untreated patients with CLL. The data support further study of this triplet regimen, which is now being assessed in a phase 3 registrational trial (ACE-CL-311), which has the potential to define acalabrutinib, venetoclax, and obinutuzumab as a new standard-of-care for previously untreated patients with chronic lymphocytic leukaemia.
