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Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial

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;...

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Main Authors: Fürstenau, Moritz (Author) , Giza, Adam (Author) , Weiss, Jonathan (Author) , Kleinert, Fanni (Author) , Robrecht, Sandra (Author) , Franzen, Fabian (Author) , Stumpf, Janina (Author) , Langerbeins, Petra (Author) , Al-Sawaf, Othman (Author) , Simon, Florian (Author) , Fink, Anna-Maria (Author) , Schneider, Christof (Author) , Tausch, Eugen (Author) , Schetelig, Johannes (Author) , Dreger, Peter (Author) , Böttcher, Sebastian (Author) , Fischer, Kirsten (Author) , Kreuzer, Karl-Anton (Author) , Ritgen, Matthias (Author) , Schilhabel, Anke (Author) , Brüggemann, Monika (Author) , Stilgenbauer, Stephan (Author) , Eichhorst, Barbara (Author) , Hallek, Michael (Author) , Cramer, Paula (Author)
Format: Article (Journal)
Language:English
Published: July 18, 2024
In: Blood
Year: 2024, Volume: 144, Issue: 3, Pages: 272-282
ISSN:1528-0020
DOI:10.1182/blood.2023022730
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2023022730
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Author Notes:Moritz Fürstenau, Adam Giza, Jonathan 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
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Summary: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.
Item Description:Gesehen am 24.02.2025
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2023022730

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