Ibrutinib Lead-in followed by Venetoclax Plus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia - SAKK 34/17.

The rationale for combining ibrutinib and venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment lies in their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. SAKK34/17 (NCT03708003) is a single-arm, open-label, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK- or BCL2-inhibitors was allowed. The lead-in phase with ibrutinib was extended to six months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD, 10-4) rate. The primary endpoint was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary endpoints included assessing the proportion of patients who transitioned to a low-risk category for TLS after receiving ibrutinib lead-in. Out of the 30 patients with R/R CLL who were enrolled, 40.0% achieved a status of uMRD CR/CRi according to the intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. Following the lead-in period with ibrutinib, 57.1% of patients achieved a low-risk for TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness.