Key message:
In the phase II CLL2-BAAG trial, the efficacy of measurable residual disease (MRD)-guided triple therapy comprising acalabrutinib, venetoclax, and obinutuzumab was evaluated in 45 patients with relapsed/refractory CLL. MRD was assessed by flow cytometry in peripheral blood, while ctDNA was examined by PCR. After 6 months of triple therapy, the rate of undetectable MRD reached 75.6%, increasing to 93.3% during a median follow-up of 36.3 months (94.4% among patients with TP53 mutations). Importantly, the 3-year progression-free survival and overall survival rates were 85.0% and 93.8%, respectively. Of the 18 MRD occurrences identified, only 5 resulted in clinical progression.
These findings underscore the effectiveness of MRD-guided therapy, highlighting its potential as a robust treatment approach and advocating for the integration of ctDNA assessment into routine clinical practice.
Summary:
The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional reduction with bendamustine in 45 patients with relapsed/refractory CLL (one patient was excluded from the analysis due to a violation of the exclusion criteria). MRD was measured by flow cytometry (FCM, undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) by digital droplet digital PCR (ddPCR) of variable-diversity-junction (VDJ) rearrangements ) and CLL-related mutations in plasma. MRD recurrence was defined as detectable ctDNA and/or MRD ≥10-4 after achieving both uMRD/undetectable ctDNA. The median number of previous treatments was 1 (range 1-4), 18 patients (40%) had received a BTK inhibitor (BTKi) and/or venetoclax before inclusion, 14/44 (31.8%) had aberrations in TP53, 34 (75.6%) had unmutated IGHV. 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 42>
The estimated three-year progression-free survival and overall survival rates were 85.0% and 93.8%. In total, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with clinical progression and 13 without) occurred after the end of treatment. Twelve were detected for the first time by ctDNA, three by FCM and three synchronously. Patients with earlier detection by ctDNA appeared to have a genetically higher risk disease. In conclusion, MRD-guided time-limited treatment with acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based assays to MRD assessment by FCM appears to improve early relapse detection.
Fountain: BioPress
