MRD-guided zanubrutinib, venetoclax and obinutuzumab in relapsed CLL: primary endpoint analysis from the CLL2-BZAG trial
Mené sur 40 patients atteints d'une leucémie lymphoïde chronique récidivante ou réfractaire, cet essai de phase II évalue l'efficacité, du point de vue du taux de maladie résiduelle mesurable dans le sang périphérique après six cycles, d'un traitement combinant zanubrutinib, vénétoclax et obinutuzumab après un traitement optionnel par bendamustine
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