Zanubrutinib/Venetoclax Continues to Impress in Treatment-Naive CLL/SLL

New extended follow-up data from the phase 3 SEQUOIA trial (NCT03336333) demonstrate that in treatment-naive patients with chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), the combination of zanubrutinib (Brukinsa) plus venetoclax (Venclexta) maintained a 36-month progression-free survival (PFS) rate of 87% (95% CI, 78.6%–92.4%), regardless of del(17p)/TP53 or immunoglobulin heavy-chain variable (IGHV) mutational status, with durable minimal residual disease (MRD) responses maintained across genomic subgroups.

“These data support the benefit of this regimen regardless of del(17p)/TP53 mutation or IGHV mutational status,” Mazyar Shadman, MD, MPH, said during a poster presentation at the 67th ASH Annual Meeting in Orlando, Florida.¹ Shadman is a professor in the clinical research division and medical director of cellular immunotherapy at the Fred Hutch Cancer Center in Seattle, Washington.

The median follow-up was 46.1 months in patients with del(17p) and/or TP53 mutation and 36.9 months in those patients without.

In patients with a del(17p) mutation regardless of a TP53 mutation, the PFS rate was 87% (95% CI, 75.6%–93.3%). In patients without the del(17p) mutation, the PFS rate was 89% (95% CI, 75.8%–95.3%).

At 36-months, those with unmutated IGHV had a PFS rate of 87% (95% CI, 76.6%–92.8%) compared with 88% (95% CI, 66.1%–95.8%) among patients with mutated IGHV.

Fixed-duration treatment is emerging as a key therapeutic option for treatment-naive patients with CLL/SLL; however, optimal treatment duration for high risk patients, including those with del(17p)/TP53 mutation or unmutated IGHV genes, remain unclear.

Study Design

The SEQUOIA trial was a randomized study with 4 treatment arms. A total of 114 nonrandomized patients in arm D with (n = 66) or without (n = 47) del(17p)/TP53 mutation received 160 mg of zanubrutinib and 400 mg of venetoclax.

“Previously, at a median follow-up of 31 months, the combination showed a 24-month PFS rate of 92% and a manageable safety profile,” Shadman said.²

Investigator-assessed end points for arm D include PFS and objective response rate. Other end points for arm D include overall survival, undetectable MRD (uMRD) rate at 10^-4 sensitivity, and safety.

Disposition and Baseline Characteristics

As of April 30, 2025, 78 (68%) patients remained on zanubrutinib, and all patients completed or discontinued venetoclax. A total of 13 patients completed zanubrutinib and/or venetoclax treatment early per uMRD-guided stopping criteria. Of these, 5 had del(17p) and/or TP53 mutation whereas 8 did not have the mutation. Eight patients remained progression-free, 3 patients with del(17p) and/or TP53 mutation progressed, and 2 withdrew from the study.

Overall, patients (n = 114) were a median age of 67 years (range, 26–87), the majority (56%) were male, and 98% were ECOG performance status of 0 or 1. Regarding genomic mutation status, 43% had a TP53 mutation, 52% had a del(17p) mutation, and 37% had both.

The majority (75%) of patients had unmutated IGHV and 41% exhibited 3 or more complex karyotype (CK) abnormalities whereas 23% exhibited 5 or more CK abnormalities.

Shadman reported the best uMRD rate in peripheral blood as 60% overall. Fifty-nine percent of patients had del(17p) and/or TP53 mutation and this was 62% in patients without the mutation.

“In patients with del(17p) and/or TP53 mutation, peripheral blood MRD increased from 15% in cycle 15 to 38% in cycle 27,” Shadman said.

After 15 cycles, uMRD rates were 15% in patients with the mutation and 40% in patients without the mutation. After 27 cycles, uMRD rates were 38% and 36%, respectively.

Safety

Shadman said safety results were consistent with previous data,² with the most common treatment-emergent adverse events (TEAEs) of any grade was COVID-19 (55%), diarrhea (43%), confusion (33%), and nausea (32%). For patients with TEAEs that were grade 3 or higher, the most common were decreased neutropenia/neutrophil count (24%), hypertension (9%), and diarrhea (6%).

The most common any grade TEAEs of special interest were infections (84%), hemorrhage (54%), neutropenia (27%), and second primary malignancies (19%). The most common grade 3 or higher TEAEs of special interest were neutropenia (24%), infections (12%), and grade 3 infections (11%).

“Zanubrutinib and venetoclax continue to demonstrated a tolerable safety profile and no new safety signals were identified,” Shadman said. “National Cancer Center Network guidelines recommend this regimen as a preferred first-line regimen for CLL/SLL,” he concluded.

REFERENCES

1. Shadman M, Munir T, Ma S, et al. Zanubrutinib + venetoclax for treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), including patients with del(17p) and/or TP53 mutation and unmutated immunoglobulin heavy-chain variable status: 3-year results from SEQUOIA arm D. Blood. 2025;146(suppl 1):5669-5669. doi:10.1182/blood-2025-5669

2. Shadman M, Munir T, Ma S, et al. Zanubrutinib and venetoclax for patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma with and without del(17p)/TP53 mutation: SEQUOIA Arm D Results. J Clin Oncol. 2025;43(21):2409-2417. doi:10.1200/JCO-25-00758