Six-Year Outcomes in CLL and SLL: Insights From the SEQUOIA and ALPINE Trials

Ian Flinn, MD, PhD; and Danielle Brander, MD, discuss how advances in targeted therapy have reshaped frontline management and reduced reliance on chemotherapy.

The conversation begins with the importance of biomarker testing in chronic lymphocytic leukemia (CLL). Brander emphasizes that despite improved therapies, baseline risk stratification remains critical due to disease heterogeneity. Key tests include fluorescence in situ hybridization analysis for del(17p) and del(11q), IGHV mutation status, TP53 mutation testing, and, in select cases, conventional karyotyping to identify complex cytogenetics. Results from these tests help predict disease behavior, time to treatment, and durability of response, and they guide therapeutic decision-making, especially in community practice.

The discussion then shifts to the current frontline treatment landscape, highlighting covalent Bruton tyrosine kinase (BTK) inhibitors and BCL2-based regimens as preferred options. Both faculty members note that chemoimmunotherapy is now rarely used, given findings from multiple randomized trials demonstrating superior progression-free survival (PFS)—and, in some cases, superior overall survival—with novel agents along with better tolerability.

Flinn reviews the SEQUOIA trial design and 6-year results. In treatment-naive patients without del(17p), zanubrutinib demonstrated markedly superior PFS compared with bendamustine-rituximab. A separate single-arm cohort of patients with del(17p) also showed durable disease control with zanubrutinib, despite higher-risk baseline features. Importantly, long-term outcomes with zanubrutinib were robust across risk groups.

Safety findings were consistent with prior experience. Atrial fibrillation and hypertension rates were low, neutropenia was more common with chemoimmunotherapy, and bleeding events were higher with BTK inhibition, reflecting known class effects. Overall, the data reinforce zanubrutinib as an effective, well-tolerated frontline option for diverse CLL populations, including those with high-risk disease.