PFS Benefit with Zanubrutinib Over Bendamustine/Rituximab Across Multiple High-Risk Factors in the Phase 3 SEQUOIA Study in Patients with Treatment-Naive CLL/SLL without del(17p)

Zanubrutinib is a Bruton tyrosine kinase inhibitor (BTKi) with high potency, selectivity, and efficacy and a favorable toxicity profile. The phase 3 SEQUOIA study (NCT03336333) demonstrated the superiority of zanubrutinib in prolonging progression-free survival (PFS) versus bendamustine/rituximab in treatment-naïve patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and without del(17p) (Cohort 1). Biomarker subgroup analysis of the patients enrolled in SEQUOIA study Cohort 1 were conducted and correlated with PFS; these results were presented at the 2023 American Society of Hematology annual meeting and summarized here.

In the SEQUOIA study, patients with CLL/SLL were randomized to receive either zanubrutinib or bendamustine/rituximab. Blood (CLL) or bone marrow (SLL) samples were used for fluorescence in situ hybridization for chromosome abnormalities, cytogenetic analysis for complex karyotype, and next-generation sequencing (NGS). Data cutoff was October 31, 2022.

A total of 479 patients without del(17p) were randomized; 241 received zanubrutinib and 238 received bendamustine/rituximab. There was similar distribution of CLL features between the 2 treatment arms. In the zanubrutinib and bendamustine/rituximab cohorts, the most frequently mutated genes associated with poor prognosis were ATM, SF3B1, NOTCH1, and BRAF.

Among patients with cytogenetic abnormalities, zanubrutinib demonstrated significantly better PFS than bendamustine/rituximab in del(11q), del(13q), trisomy 12, or CKT ≥3 cohorts. A similar PFS benefit was conferred with zanubrutinib treatment in del(11q) or trisomy 12 cohorts compared to those without these abnormalities. In the zanubrutinib-treated cohort, CKT ≥3 was not associated with worse PFS compared to without (P=.18).

Zanubrutinib provided significant PFS benefit compared to bendamustine/rituximab therapy in patients with either mutated IGHV (mIGHV) or unmutated IGHV (uIGHV). Moreover, IGHV mutational status did not impact PFS in zanubrutinib-treated patients (P=.12). In the uIGHV cohort, IGHV1-69 was the most prevalently expressed clone in both arms; zanubrutinib provided significantly better PFS compared to bendamustine/rituximab in this subgroup (P=.0048).

Among patients with mutated genes, significantly better PFS was derived with zanubrutinib than with bendamustine/rituximab (ATM [P=.02], BRAF [P=.01], NOTCH1 [P<.001], SF3B1 [P<.001]). Also, similar PFS was observed in zanubrutinib-treated patients with or without these mutations.

These results indicate that zanubrutinib treatment was associated with superior PFS in all biomarker subgroups analyzed, including del11q, CKT ≥3, and uIGHV compared to bendamustine/treatment, with comparable PFS benefit derived by zanubrutinib patients with or without those markers.


Ramakrishnan V, Xu L, Paik J, et al. Broad superiority of zanubrutinib (Zanu) over bendamustine + rituximab (BR) across multiple high-risk factors: biomarker subgroup analysis in the phase 3 SEQUOIA study in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without del(17p). Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Poster 1902

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