Novel BTK/BCL2 Inhibitor Combination Shows Efficacy in TP53-Aberrant CLL
The SEQUOIA arm D study demonstrates promising outcomes for treatment-naive patients with CLL, including high-risk patients.
The combination of BCL2 and Bruton tyrosine kinase (BTK) inhibitors has shown promising efficacy in chronic lymphocytic leukemia (CLL); however, data for patients with CLL carrying del(17p) and/or TP53 mutations (TP53mut) have been limited in prior studies. To address this critical gap, the SEQUOIA arm D cohort specifically investigated the combination of zanubrutinib (Brukinsa) and venetoclax (Venclexta) in a large population of treatment-naive patients with TP53-aberrant CLL/small lymphocytic lymphoma (SLL).
In an interview with Targeted OncologyTM, Mazyar Shadman, MD, MPH, Fred Hutch Cancer Center and University of Washington, discusses the findings.
The nonrandomized arm D cohort enrolled 114 treatment-naive patients, including 66 (58%) with TP53-aberrant disease and 47 (41%) without, along with 1 patient with missing TP53 results. Patients initiated zanubrutinib from cycle 1, followed by a venetoclax ramp-up from cycle 4 through cycle 28. Following this fixed-duration combination, patients continued with zanubrutinib monotherapy until disease progression, unacceptable toxicity, or achievement of undetectable minimal residual disease (uMRD)-guided stopping criteria.
At a median follow-up of 31.2 months, 75% of patients remained on zanubrutinib monotherapy, indicating a high rate of treatment continuation. Impressively, 59% of patients in the intention-to-treat population achieved peripheral blood undetectable measurable residual disease (uMRD). The 24-month progression-free survival (PFS) estimate was 92% (95% CI, 85%-96%), demonstrating durable disease control.
The most common any-grade treatment-emergent adverse events (TEAEs) included COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). Common grade ≥3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).
The study concluded that the combination of zanubrutinib and venetoclax demonstrated impressive efficacy and a favorable safety profile in treatment-naive CLL/SLL patients. Crucially, these positive outcomes were observed irrespective of the presence of TP53-aberrant disease, suggesting this regimen could offer a valuable, chemotherapy-free treatment option for a broader range of treatment-naive patients with CLL/SLL, particularly those with high-risk genetic features.
