Zanubrutinib-Venetoclax Pairing Yields Encouraging Efficacy in TN CLL/SLL

A combination treatment of zanubrutinib (zanu) and venetoclax (ven) showed strong and sustained clinical impact with profound response depth in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), including large subgroups with or without del(17p) and/or TP53 mutation, according to data presented at the 2025 ASCO Annual Meeting.

The Arm D nonrandomized cohort of the SEQUOIA study in patients aged 65 years or older, or patients aged 18-64 years with comorbidities, has demonstrated promising safety and effectiveness in treating TN CLL/SLL, according to Mazyar Shadman, MD, MPH, of the Fred Hutchinson Cancer Center.

Dr. Shadman and colleagues analyzed 114 patients in the cohort between November 2019 and July 2022, including 66 (58%) with del(17p) and/or TP53 mutation, 47 (41%) without del(17p) and TP53 mutation, and one with missing TP53 results.

Patients in the cohort received 160 mg of zanu twice daily and 400 mg of ven once daily (after a ramp-up), followed by continuous zanu monotherapy until the occurrence of progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)– guided stopping rules.

The results were highly encouraging, with an observed PFS in patients with del(17p) and/or TP53 mutation of 94% (and maintained at 36 months in 88% of patients), and 89% in patients without del(17p) and TP53 mutation.

The most common reasons for early discontinuation of treatment were reaching the uMRD-guided early stopping rules (zanu: 7%; ven: 7%), adverse events (AEs) (zanu: 8%; ven: 6%), and PD (zanu: 5%; ven: 4%). Of six patient deaths, five were due to nontreatment-related AEs, and one was due to PD. Patients with or without del(17p)/TP53 mutation achieved similar efficacy responses and best PB uMRD.

The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and a decreased neutrophil count (6%). However, no cardiac or COVID-19-related deaths were observed.

Overall, this data highlights the potential for a new therapy, structured around zanubrutinib, to enable effective long-term containment of disease, regardless of mutational status, in TN CLL/SLL patients.

Disclosure: BeiGene provided funding for this study.