Time-Limited Zanubrutinib Plus Venetoclax: MRD-Guided Outcomes from SEQUOIA Arm D

In this segment, Dr. Brander reviews results from Arm D of the SEQUOIA trial, which evaluated a fixed-duration, MRD-guided combination of zanubrutinib and venetoclax in previously untreated patients with CLL/SLL. This arm was designed to explore whether deep, durable responses could be achieved with time-limited therapy across both standard- and high-risk populations.

Arm D initially enrolled patients with high-risk disease features, including del(17p) and TP53 abnormalities, and later expanded to include patients with other risk markers. All participants began with a zanubrutinib lead-in for 3 cycles, followed by the addition of venetoclax with standard tumor lysis syndrome ramp-up. Treatment duration was individualized: patients were required to complete minimum exposure thresholds but could discontinue combination therapy if they achieved complete response and sustained undetectable MRD in both blood and bone marrow on consecutive assessments. Patients who did not meet stopping criteria could continue zanubrutinib.

Baseline characteristics were balanced between risk groups, with a median age in the mid-60s and a substantial proportion of patients with bulky disease and complex karyotypes. Importantly, PFS outcomes were similar regardless of TP53 or del(17p) status. At 36 months, PFS was 87% in patients with TP53 aberrations and 89% in those without, with comparable results at 42 months of follow-up. Outcomes were also similar between patients with mutated and unmutated IGHV, a notable finding given prior fixed-duration studies showing shorter PFS in IGHV-unmutated disease.

MRD analyses suggested that responses may deepen with longer combination therapy, particularly in high-risk patients. Rates of undetectable MRD increased substantially between cycles 15 and 27 in patients with TP53 or del(17p), indicating potential benefit from extended treatment duration in this group. Although follow-up off therapy remains relatively short, responses have largely been maintained to date.

Safety findings were consistent with known profiles of BTK and BCL2 inhibitors, with no unexpected adverse events observed. Overall, Arm D supports the feasibility of MRD-guided, time-limited combination therapy as an effective strategy across CLL risk groups.