MRD-Guided Zanubrutinib, Venetoclax and Obinutuzumab Maintenance in Relapsed/Refractory CLL

The phase 2 CLL2-BZAG study evaluated the measurable residual disease (MRD)-guided triple combination of Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib, BCL2 inhibitor venetoclax, and anti-CD20 monoclonal antibody obinutuzumab following an optional bendamustine debulking in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL); treatment duration was based on detection of MRD to tailor therapy to the diverse needs of differently pretreated patients. Efficacy data and circulating tumor DNA (ctDNA) analyses of the CLL2-BZAG study were reported at the 2023 American Society of Hematology annual meeting and summarized here.

As induction therapy, patients received obinutuzumab (Cycle 1; days 1/2, 8, 15; Cycle 2-3, monthly) plus zanibrutinib (Cycle 2) and venetoclax (Cycle 3) with a dose ramp-up over 5 weeks; maintenance with continuous zanubrutinib and venetoclax and 3-month obinutuzumab was administered either until achievement of a deep remission with undetectable MRD <10-4 (uMRD) in peripheral blood (PB) or for up to 24 months. The primary end point was uMRD rate by flow cytometry in PB after 6 months of triple therapy at final restaging.

A total of 40 evaluable patients with relapsed/refractory CLL were included in the current analysis. Median age of total cohort was 64 years. Patients received a median of 1.7 prior lines of therapy; 45% had received prior BTKi, 7 patients received venetoclax (17.5%). 12.5% of patients had a del(17p) mutation, 37.5% has a del(11q) mutation, 77.5% had unmutated IGHV, and 37.5% had deleted and/or mutated TP53.

At final restaging, all patients achieved responses and 21 (52.5%) achieved uMRD in PB. The rate of uMRD was similar in the cohort with TP53 aberrations (80%) and in the cohort with venetoclax and/or BTKi pretreatment (80%). After a median observation time of 21.5 months, the estimated 18-month PFS was 96% and 18-month overall survival rate was 96.8%.

At a median of 21.5 months, 63 patients experience a grade 3/4 adverse event. The most common grade ≥3 adverse events (AEs) were neutropenia (n=10), COVID-19 (n=9), thrombocytopenia (n=7), and pneumonia (n=5); 2 patients experienced grade ≥3 cardiac AEs (grade 3 non-ST-elevation myocardial infarction and grade 3 atrial fibrillation).

Based on these results, it was concluded that MRD-guided triple combination of zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in patients with R/R CLL, including those previously treated with BTKi and/or venetoclax.


Furstenau M, Giza A, Schneider C, et al. MRD-Guided zanubrutinib, venetoclax and obinutuzumab after an optional debulking with bendamustine in patients with relapsed/refractory chronic lymphocytic leukemia: primary endpoint analysis of the phase 2 CLL2-BZAG study. Presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition, December 9-12, 2023; San Diego, CA: Poster 1897.

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