My Treatment Approach: Shared Decision-Making in CLL: Balancing Safety, Efficacy, and Patient Preference in CLL - Episode 3
Expert Insights: Exploring Efficacy Differences in CLL MRD Rates Between the Fixed-Duration BTKi + BCL2i Regimens
Panelists discuss how CLL treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while noting that ibrutinib-venetoclax combinations may still have advantages due to increased venetoclax exposure and deeper responses, particularly as the field moves toward time-limited therapies that reduce long-term toxicities and financial burden.
This segment examines the efficacy differences between various fixed-duration Bruton tyrosine kinase inhibitor (BTKi) plus BCL-2 inhibitor combinations in chronic lymphocytic leukemia (CLL), with particular focus on minimal residual disease (MRD) rates as a key outcome measure. The discussion highlights that while oral doublets offer practical advantages, they demonstrate lower MRD rates compared with antibody-containing regimens. Importantly, patient-level MRD rates appear to significantly impact progression-free survival outcomes, making this a critical consideration in treatment selection, especially for younger patients who may benefit from fixed-duration approaches.
The experts compare different BTKi combinations, noting significant differences in MRD achievement rates. The CAPTIVATE trial data for ibrutinib plus venetoclax (12-month fixed duration) and FLAIR trial results (MRD-driven duration) show impressive outcomes. In contrast, the AMPLIFY trial examining acalabrutinib plus venetoclax demonstrated lower MRD undetectability rates compared with ibrutinib-venetoclax combinations. This difference may be attributed to ibrutinib’s ability to increase venetoclax exposure, potentially enhancing the combination’s efficacy. The superior MRD rates with ibrutinib-venetoclax (above 90% using 10-4 cutoff) suggest this combination may offer deeper responses than other oral doublets.
The discussion reveals emerging recognition that MRD status impacts outcomes even in favorable patient subgroups, such as those with mutated IGHV. While acalabrutinib-venetoclax is expected to receive FDA approval first in the United States, European colleagues express enthusiasm for ibrutinib-venetoclax based on their clinical experience in optimizing patient selection. The experts suggest there may still be a role for ibrutinib-venetoclax in select patients, particularly given that fixed-duration use (1 year) significantly reduces the risk of long-term cardiovascular adverse effects associated with continuous ibrutinib therapy, while potentially maintaining superior efficacy through deeper MRD responses.
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