Breaking Barriers: Future Directions in CLL/SLL Treatment

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The AMPLIFY study represents a landmark phase 3 trial comparing acalabrutinib-plus-venetoclax combinations with physician’s choice chemoimmunotherapy in treatment-naive patients with CLL. Importantly, the study excluded patients with deletion 17p and TP53 mutations, limiting generalizability to high-risk populations. The 3-year follow-up demonstrated expected superiority over chemoimmunotherapy, with doublet and triplet arms showing impressive progression-free survival rates, although the triplet arm (adding obinutuzumab) showed approximately 10% improvement over the doublet approach.

Safety considerations emerged as a significant concern, particularly for the triplet combination, which showed doubled rates of COVID-19 deaths compared with the doublet arm, raising important questions about infection risk stratification. The increased infection risk associated with intensified therapy requires careful patient selection and may not be appropriate for all comers. This safety signal emphasizes the importance of balancing efficacy gains with toxicity risks, particularly in an era where effective retreatment options exist for most patients.

Future directions in CLL treatment include exploration of alternative BCL2 inhibitors, such as sonrotoclax in the randomized phase 3 CELESTIAL study comparing it with venetoclax plus obinutuzumab. The upcoming MAGIC study will provide measurable residual disease (MRD)–driven treatment strategies comparing acalabrutinib plus venetoclax to the established venetoclax-plus-obinutuzumab combination. These studies feature venetoclax plus obinutuzumab as comparator arms rather than chemoimmunotherapy, potentially providing more relevant practice-changing data for contemporary CLL management and helping define the optimal role of MRD guidance in treatment decision-making.