Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial
Moritz Fürstenau, Adam Giza, Jonathan M. Weiss, Fanni Kleinert, Sandra Robrecht, Fabian Franzen, Janina Stumpf, Petra Langerbeins, Othman Al‐Sawaf, Florian Simon, Anna‐Maria Fink, Christof Schneider, Eugen Tausch, Johannes Schetelig, Peter Dreger, Sebastian Böttcher, Kirsten Fischer, Karl‐Anton Kreuzer, Matthias Ritgen, Anke Schilhabel, Monika Brüggemann, Stephan Stilgenbauer, Barbara Eichhorst, Michael Hallek, Paula Cramer
Abstract
ABSTRACT: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264.