Long-term zanubrutinib efficacy in high-risk CLL/SLL patients with del(17p)

5-year follow-up data from the SEQUOIA trial confirmed the durable efficacy and tolerability of zanubrutinib in treatment-naive participants with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) harbouring deletion of the 17p chromosome (del[17p]), a subgroup historically associated with poor prognosis.

The updated analysis of Arm C of the phase 3 SEQUOIA study (NCT03336333), presented by Prof. Constantine Tam (Monash University, Australia), reported on 111 participants with del(17p)-harbouring CLL/SLL who received first-line Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib monotherapy [1, 2]. At a median follow-up of nearly 66 months, median progression-free survival (PFS) and overall survival (OS) had not yet been reached. The estimated 5-year PFS rate was 72.2%, rising to 73.0% following adjustment for COVID-19-related variables. The 5-year OS rate was 85.1%, or 87.0% after adjusting for COVID-related factors. These outcomes mirror those seen in participants with CLL/SLL  without del(17p) who were treated with zanubrutinib in the same trial, suggesting that zanubrutinib may mitigate the historically adverse impact of this high-risk genetic feature.

The overall response rate reached 97.3%, with 18.2% of participants achieving a complete response or a complete response with incomplete haematologic recovery. The trial cohort had a median age of 71 years and included a high proportion of participants with other adverse-risk features, such as unmutated IGHV (60%) and TP53 mutations (42%). Notably, the majority of participants (62.2%) remained on treatment at the time of analysis. Discontinuations were primarily due to adverse events (17.1%) or disease progression (15.3%).

No new safety signals were observed. The most common adverse events of any grade included infections (82%), bleeding events (60%), and neutropenia (19%). Grade ≥3 adverse events were consistent with the known safety profile of BTK inhibitors, and included infections (33%), neutropenia (16%), and hypertension (8%).

Prof. Tam pointed out that this is the most extensive prospective study of its kind in del(17p)-harbouring CLL/SLL. He concluded by placing the findings in context: “Zanubrutinib appears to neutralise the poor prognostic implications traditionally linked to del(17p). Furthermore, the scale and maturity of this dataset exceed existing experiences with other BTK inhibitors in this population, including ibrutinib and acalabrutinib.”

1. Tam CS, et al. SEQUOIA 5-year follow-up in arm C: Frontline zanubrutinib monotherapy in patients with del(17p) and treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Abstract #7011, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Tam CS, et all. Lancet Oncol. 2022 Aug;23(8):1031–1043.

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Posted on 30 July 2025