Zanubrutinib-Venetoclax-Obinutuzumab Achieves 85% Undetectable MRD in Relapsed CLL
The CLL2-BZAG phase 2 trial demonstrated that MRD-guided zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in 40 relapsed/refractory CLL patients, including 45% previously exposed to BTK inhibitors. Best undetectable MRD rate reached 85%, with estimated 18-month progression-free and overall survival both at 96%. This trial extends the evidence for MRD-guided fixed-duration triple combinations in CLL and is notable for including patients previously treated with both BTK inhibitors and venetoclax.
The original study
MRD-guided zanubrutinib, venetoclax, and obinutuzumab in relapsed CLL: primary end point analysis from the CLL2-BZAG trial.
- Authors
- Fürstenau M, Robrecht S, Schneider C, Tausch E, Giza A, Ritgen M, et al.
- Journal
- Blood
- Type
- Journal Article, Clinical Trial, Phase II, Multicenter Study
- PMID
- 39883943
Original abstract
The phase 2 CLL2-BZAG trial tested a measurable residual disease (MRD)-guided combination treatment of zanubrutinib, venetoclax, and obinutuzumab after an optional bendamustine debulking in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). In total, 42 patients were enrolled and 2 patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of 1 prior therapy (range, 1-5); 18 patients (45%) had already received a Bruton tyrosine kinase (BTK) inhibitor (BTKi); 7 patients (17.5%) venetoclax; and, of these, 5 (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion, and 31 (77.5%) had unmutated immunoglobulin heavy chain variable region gene. With a median observation time of 21.5 months (range, 8.0-35.3) the most common adverse events were COVID-19 (n = 26 patients), diarrhea (n = 15), infusion-related reactions (n = 15), thrombocytopenia (n = 14), nausea (n = 12), fatigue (n = 12), and neutropenia (n = 12). Two patients had fatal adverse events (COVID-19, and fungal pneumonia secondary to COVID-19). After 6 months of the triple combination, all patients responded, and 21 (52.5%; 95% confidence interval, 36.1-68.5) showed undetectable MRD (uMRD) in the peripheral blood. In many patients, remissions deepened over time, with a best uMRD rate of 85%. The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%, respectively. No patient has yet required a subsequent treatment. In summary, the MRD-guided triple combination of zanubrutinib, venetoclax, and obinutuzumab induced deep remissions in a relapsed CLL population enriched for patients previously treated with a BTKi/venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT04515238.