MRD-guided zanubrutinib, venetoclax and obinutuzumab in relapsed CLL: primary endpoint analysis from the CLL2-BZAG trial

• An MRD-guided treatment with zanubrutinib, venetoclax and obinutuzumab achieved deep remissions in a majority of patients with relapsed CLL

• Apart from COVID-19-related adverse events, the triple combination was well tolerated

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 CLL. In total, 42 patients were enrolled and two patients with ≤2 induction cycles were excluded from the analysis population per protocol. Patients had a median of one prior therapy (range 1-5), 18 patients (45%) had already received a BTK inhibitor (BTKi), seven patients (17.5%) venetoclax, and of these, five (12.5%) had received both. Fifteen patients (37.5%) had a TP53 mutation/deletion and 31 (77.5%) had unmutated IGHV. 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, fungal pneumonia secondary to COVID-19). After six months of the triple combination all patients responded and 21 (52.5%, 95% confidence interval 36.1%-68.5%) showed uMRD in peripheral blood. In many patients remissions deepened over time with a best uMRD rate of 85%. The best uMRD rate was similar in patients with TP53 aberrations (80%) and patients previously exposed to venetoclax/BTKi (80%). The estimated progression-free and overall survival rates at 18 months were 96% and 96.8%. 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. ClinicalTrials.gov NCT04515238