Expert Insights: Emerging Combination Strategies in Treatment-Naive CLL

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The treatment landscape for frontline chronic lymphocytic leukemia (CLL) has expanded from a single time-limited option (obinutuzumab plus venetoclax) to include emerging Bruton tyrosine kinase (BTK) inhibitor-plus-venetoclax combinations, particularly following AMPLIFY trial results. However, cardiac safety concerns with first-generation ibrutinib combinations led to the development of second-generation BTK inhibitor combinations like acalabrutinib plus venetoclax. The AMPLIFY trial represents the first large phase 3 data set for second-generation BTK inhibitor–based fixed-duration therapy, although longer-term follow-up data remain limited compared with established regimens.

Current practice regarding newer combinations requires careful patient selection and informed consent discussions due to limited long-term follow-up data. The 36-month follow-up threshold represents a minimum benchmark for considering treatment regimens in clinical practice, significantly shorter than the 5 to 9 years of data available for established therapies. Appropriate candidates for these newer combinations include highly motivated patients specifically requesting oral-only regimens with defined treatment end points, representing a minority of current patients with CLL.

Future combination strategies must address fundamental questions about optimal treatment duration, measurable residual disease–guided therapy decisions, and management of high-risk patients with deletion 17p (del 17p). The SEQUOIA Arm D data showing similar outcomes between del 17p and wild-type patients are promising, but the continuation of zanubrutinib monotherapy in many high-risk patients complicates interpretation as a truly fixed-duration approach. Longer follow-up from all combination strategies will be essential to determine optimal treatment durations and retreatment strategies for the evolving landscape of CLL combination therapy.