Patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) who carry deletion 17p (del(17p)) and/or TP53 mutations represent a biologically high-risk subgroup with historically poor outcomes when treated with chemoimmunotherapy. Although Bruton tyrosine kinase (BTK) inhibitors have improved prognosis in this population, long-term disease control has remained challenging. A pooled analysis published in Blood Advances evaluated the efficacy and safety of zanubrutinib, a next-generation BTK inhibitor, in treatment-naive and relapsed/refractory patients with del(17p) and/or TP53-mutated CLL/SLL.
Zanubrutinib was designed to provide sustained and selective BTK inhibition with reduced off-target activity compared with first-generation agents. The current analysis pooled patient-level data from three clinical studies: SEQUOIA, a phase 3 trial in treatment-naive CLL/SLL; ALPINE, a phase 3 trial comparing zanubrutinib with ibrutinib in relapsed or refractory disease; and AU-003, a phase 1/2 study evaluating zanubrutinib across multiple B-cell malignancies. The objective was to characterise long-term outcomes specifically in patients with del(17p) and/or TP53 mutations across treatment settings.
CLINICAL SUMMARY
What was examined
A pooled analysis of three clinical trials assessed the efficacy and safety of zanubrutinib in CLL/SLL patients with del(17p) and/or TP53 mutations across frontline and relapsed/refractory settings.
Key findings
-
In treatment-naive patients, estimated 60-month PFS and OS were 70.7% and 82.3%, with median survival not reached.
-
In relapsed or refractory disease, 36-month PFS was higher with zanubrutinib than with ibrutinib (59.2% vs 38.5%), with similar OS between treatments.
Clinical implications
-
Zanubrutinib provides durable disease control in patients with high-risk CLL/SLL genetic features traditionally associated with poor outcomes.
-
These data support zanubrutinib as an effective option for del(17p)/TP53-mutated disease, while highlighting the need for prospective validation.
In total, 301 patients with high-risk CLL/SLL were included, comprising 132 treatment-naive patients and 169 with relapsed or refractory disease. In the SEQUOIA trial, treatment-naive patients with del(17p) and/or TP53 mutations were followed for a median of 64.8 months. Median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 60-month PFS rate was 70.7%, and the estimated 60-month OS rate was 82.3%, indicating durable disease control in a population traditionally associated with early relapse.
In the relapsed or refractory setting, outcomes were assessed primarily using data from the ALPINE trial. After approximately 39 months of follow-up, the estimated 36-month PFS rate among patients with del(17p) and/or TP53 mutations was 59.2% with zanubrutinib, compared with 38.5% among those treated with ibrutinib. Overall survival at 36 months was similar between the two treatment groups, at 73.6% with zanubrutinib and 72.5% with ibrutinib. These findings suggest improved disease control with zanubrutinib relative to ibrutinib in this genetically defined high-risk population, without a clear separation in OS at this time point.
Featured Event
High response rates were observed across trials. In SEQUOIA, the overall response rate among treatment-naive patients with del(17p) and/or TP53 mutations was 96.9%. In ALPINE, the response rate was higher with zanubrutinib than with ibrutinib (89.3% vs 76.0%), and responses deepened over time. In the smaller AU-003 cohort, long-term follow-up showed continued disease control in a subset of patients, although progression events accumulated with extended observation.
The safety profile of zanubrutinib in this pooled analysis was consistent with prior reports. The most frequently observed non-haematologic adverse events included infections (notably COVID-19 and upper respiratory tract infections), arthralgia, diarrhoea, and contusions. No new safety signals emerged in patients with del(17p) and/or TP53 mutations, and treatment discontinuation due to adverse events was infrequent.
Importantly, the analysis suggests that the presence of del(17p) and/or TP53 mutations did not appear to diminish the long-term efficacy of zanubrutinib to the extent historically seen with earlier therapies. PFS outcomes in this subgroup were broadly comparable to those reported in broader zanubrutinib-treated CLL/SLL populations, supporting the drug’s activity in genetically high-risk disease.
The authors note several limitations, including the post hoc nature of the analysis, the pooling of data from trials with different designs and comparators, and limited patient numbers in some subgroups. As such, while the findings are compelling, they should be interpreted as descriptive rather than definitive. Prospective studies specifically powered for high-risk molecular subsets would help clarify the optimal role of zanubrutinib in patients with del(17p) and/or TP53-mutated CLL/SLL.
Paper: Constantine, S.T., et al. Zanubrutinib for the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies. Blood Adv (2026) 10 (3): 694–706. Access online here.
