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

• Longer ibrutinib lead-in phase decreases TLS risk and a minimum of 24-month IV combination enhances uMRD CR/CRi rates.

• Plasma ctDNA did not provide additional insights to Ig HTS MRD assessment.

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.