Photo Credit: Nemes Laszlo
Zanubrutinib plus venetoclax showed promising efficacy and manageable safety in treatment-naïve CLL/SLL, including patients with del(17p) and TP53 mutations.
At the 2025 ASCO Annual Meeting, Mazyar Shadman, MD, MPH, and colleagues presented findings from arm D of the SEQUOIA study, in which they evaluated zanubrutinib plus venetoclax in treatment-naïve patients with CLL/SLL.
“Several CLL studies have demonstrated promising efficacy with the combination of B-cell lymphoma 2 and Bruton tyrosine kinase inhibitors; however, patients with del(17p)/TP53 mutation comprised a small percentage of or were excluded from study populations,” Dr. Shadman and colleagues wrote.
In arm D, adults aged 65 years or older—or 18–64 years with comorbidities—received 160-mg zanubrutinib twice daily. Venetoclax was introduced at cycle 4 and ramped to 400 mg once daily through cycle 28, after which patients continued zanubrutinib until progression, unacceptable toxicity, or fulfillment of undetectable minimal residual disease (uMRD)–guided stopping rules. Investigator‑assessed responses were performed every three cycles to cycle 28 and every six cycles thereafter.
From November 2019 to July 2022, 114 patients were enrolled: 66 (58%) harbored del(17p) and/or TP53 mutation, 47 (41%) lacked both mutations, and TP53 status was missing for one patient. Median age was 67 years (range, 26–87); 56% were male, 75% had unmutated IGHV, and 41% carried a complex karyotype (≥3 abnormalities).
At the cutoff date in September 2024, 85 patients (75%) remained on therapy. Early discontinuation occurred for uMRD‑guided stopping (7% for each drug), adverse events (zanubrutinib 8%, venetoclax 6%), or progressive disease (zanubrutinib 5%, venetoclax 4%). Six deaths were reported, five from causes unrelated to study treatment and one from disease progression.
The researchers found that efficacy was comparable irrespective of del(17p)/TP53 status. Overall response and complete response/complete response with incomplete marrow recovery rates were similar, and both cytogenetic subgroups achieved the best peripheral‑blood uMRD.
Treatment‑emergent adverse events were manageable, according to the findings. Any‑grade COVID‑19 (54%), diarrhea (41%), contusion (32%), and nausea (30%) predominated, whereas grade 3 and higher events were chiefly neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).
No new safety signals emerged relative to prior zanubrutinib experience.
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