The Evolving Role of Retreatment With Venetoclax-Based Regimens in CLL

The Evolving Role of Retreatment with Venetoclax-Based Regimens in CLL

The growing utilization of venetoclax-based fixed-duration therapy in the frontline setting has made retreatment strategies an increasingly important clinical consideration. Although historical data from small patient cohorts suggested that venetoclax retreatment could be effective, particularly in the relapsed setting with regimens like venetoclax-rituximab from the Murano study, more robust evidence is now emerging. The REVENGE trial represents the first systematic study addressing venetoclax retreatment, examining 2 distinct patient cohorts: those experiencing progression more than 2 years after completing fixed-duration therapy, and those progressing within 1 to 2 years of treatment completion. This biological distinction is crucial as it may reflect different resistance mechanisms and treatment sensitivities.

Initial data from the REVENGE trial’s first cohort demonstrate encouraging efficacy for venetoclax retreatment in patients who progressed more than 2 years after completing initial fixed-duration therapy. Among the first 25 patients treated, the vast majority achieved excellent responses to retreatment, with 6 patients achieving undetectable minimal residual disease at the 10–6 level. These findings provide significant confidence in the fixed-duration treatment paradigm by demonstrating that patients can complete time-limited therapy and still maintain the ability to achieve comparable or potentially superior responses upon retreatment. Although longer follow-up and larger patient numbers are necessary, these early results offer reassurance to clinicians and patients considering fixed-duration approaches.

The anticipated approval of acalabrutinib plus venetoclax combination therapy introduces new questions about postprogression treatment strategies in a largely data-free environment. Treatment decisions after progression on oral doublet therapy will likely require extrapolation from venetoclax monotherapy retreatment data and CAPTIVATE study results, where patients progressing after ibrutinib plus venetoclax treatment could be assessed. The absence of data comparing outcomes after first-generation vs second-generation BTK inhibitor combinations creates additional uncertainty. For patients progressing on acalabrutinib plus venetoclax, resistance mutation testing will be essential to determine whether continued BTK inhibitor therapy might be effective, with treatment decisions guided by mutation patterns rather than established clinical trial data until more comprehensive evidence becomes available.