Dr Tedeschi on the Initial Efficacy of Zanubrutinib Plus Venetoclax in Del 17p/TP53–Mutant CLL/SLL

Alessandra Tedeschi, MD, consultant, hematology, Department of Hematology, Niguarda Hospital, Milan, Italy, discusses preliminary results from arm D of the phase 3 SEQUOIA trial (NCT03336333) investigating zanubrutinib (Brukinsa) plus venetoclax (Venclexta) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) harboring deletion 17p and/or TP53 mutations.

Findings from this cohort were presented at the 2024 EHA Hybrid Congress, and showed deep and durable responses with the combination among response-evaluable patients in this high-risk population (n = 65), Tedeschi reports. The overall response rate reached 100%, with 48% of patients experiencing either a complete response (CR) or CR with incomplete hematopoietic recovery, she details. Additionally, 59% of patients achieved undetectable minimal residual disease in at least 1 peripheral blood sample at a median follow-up of 31.6 months. The median progression-free survival (PFS) was not reached, but the 12-month and 24-month PFS estimates were 95% and 94%, respectively.

The safety profile of the combination remained consistent with that of its individual components, with no new safety signals identified, Tedeschi continues. Common all-grade non-hematologic treatment-emergent adverse effects (TEAEs) included infections (71%), COVID-19 (55%), diarrhea (39%), nausea (30%), and contusions (29%). Grade 3 or higher non-hematologic TEAEs were observed in 44% of patients, with infections (15%), diarrhea (9%), hypertension (8%), and second primary malignancies (8%) being the most frequent. Hematologic toxicity primarily involved neutropenia, which occurred in 22% of patients overall and 17% at grade 3 or higher. Notably, the proportion of patients at high risk for tumor lysis syndrome (TLS) decreased significantly from 35% at screening to 3% after three cycles of lead-in zanubrutinib, and no TLS cases were reported. Although neutropenia was slightly higher, this was expected given the combination of therapies and did not correlate with an excess of infections.

Compared with the current standard of ibrutinib (Imbruvica) and venetoclax, the addition of the next-generation BTK inhibitor zanubrutinib to venetoclax confers a better safety profile and deeper, prolonged responses, she concludes.