ctDNA Outperforms Flow Cytometry for Early Relapse Detection in CLL Triple-Combination Therapy
Final analysis of the CLL2-BAAG trial showed that MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved undetectable MRD in 93.3% of 45 relapsed/refractory CLL patients, including those with prior BTK inhibitor exposure and TP53 aberrations. Among 18 MRD recurrences detected post-treatment, ctDNA identified 12 relapses before flow cytometry, while only 3 were detected first by flow cytometry. These findings suggest ctDNA-based monitoring meaningfully complements conventional flow cytometry for earlier detection of disease recurrence.
The original study
Acalabrutinib, venetoclax, and obinutuzumab in relapsed/refractory CLL: final efficacy and ctDNA analysis of the CLL2-BAAG trial.
- Authors
- Fürstenau M, Giza A, Weiss J, Kleinert F, Robrecht S, Franzen F, et al.
- Journal
- Blood
- Type
- Journal Article, Clinical Trial, Phase II, Multicenter Study, Research Support, Non-U.S. Gov't
- PMID
- 38620072
Original 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.