Efficacy of 2nd-line treatment in CLL after venetoclax-based 1st-line treatment: Results from the GAIA/CLL13 trial

Abstract Background: Data on 2nd line treatment outcome for chronic lymphocytic leukemia (CLL) after initial venetoclax-based therapy is scarce as most patients reported in clinical trials for relapsed or refractory CLL (RR-CLL) have received chemoimmunotherapy in prior lines of therapy. Retreatment with fixed-duration venetoclax-rituximab in relapsed CLL (n=25) yielded a median PFS of ~2 years, roughly matching treatment duration (Kater et al., Blood, 2025: Murano trial). For BTK inhibitor monotherapy after progression on venetoclax-based therapy, 34-months median PFS was reported for 23 patients (Lin et al., Blood, 2020). We report efficacy outcomes for 177 patients receiving 2nd-line treatment after prior reporting of progression in the GAIA/CLL13 trial. Methods: In the GAIA/CLL13 trial, 926 physically fit patients with CLL and without TP53 aberration were randomized between 1st-line treatment with chemoimmunotherapy (CIT, n=229), rituximab-venetoclax (RV, n=237), obinutuzumab-venetoclax (GV, n=229), and GV-ibrutinib (GIV, n=231). For 177 patients with progression of CLL and indication for treatment assessed by the treating physician per iwCLL criteria (13 patients with Richter's transformation and 6 patients receiving subsequent CLL treatment without reporting progression were excluded), type of treatment, time to next (i.e. 3rd-line) treatment (TTNT2), treatment(i.e. 3rd-line)-free survival (TFS2) and overall survival (OS2) were analyzed from start of 2nd-line treatment. Type of 2nd-line treatment was divided into CIT, BTK inhibitor-based (+/- CD20 mab), venetoclax-based (+/- CD20 mab) and venetoclax + BTK inhibitor (+/- CD20 mab). Results: Of the 177 patients receiving next-line therapy, 65, 63, 32, and 17 had received CIT, RV, GV, and GIV, respectively, as 1st-line treatment. Time between iwCLL disease progression and initiation of 2nd-line treatment was similar across treatment arms with a median of 14.5 (GIV), 11.4 (GV), 12.8 (RV), and 10.1 months (CIT). Among 177 patients receiving 2nd-line treatment according to investigator's choice, 174 fell into 4 main groups: CIT (n=7), BTK inhibitor-based (n=91), venetoclax-based (n=45), and venetoclax plus BTK inhibitor (n=31). The remaining 3 received rituximab (for autoimmune disorders, n=2) or R-CHOEP (for hemophagocytic lymphohistiocytosis, n=1). No significant difference in TTNT2 was seen between patients who had received CIT or venetoclax-based therapy in 1st-line with 2-year TTNT2 rates of 85.6% and 86.1%. The 13 patients with progression as Richter's transformation received R-CHOP-like therapy (n=8), ABVD-like therapy (n=2), brentuximab, rituximab-venetoclax or allogeneic stem cell transplant (n=1 each). For patients who had received CIT in 1st-line treatment, 1 received CIT again, 34 received BTK inhibitor-based, 22 received venetoclax-based, and 5 received venetoclax + BTK inhibitor therapy. For the 112 patients who had received venetoclax-based therapy in 1st-line, 6 received CIT, 57 received BTK inhibitor-based, 23 received venetoclax-based, and 26 received venetoclax + BTK inhibitor as 2nd-line treatment. Of the 26 patients receiving venetoclax + BTK inhibitor as 2nd-line treatment after 1st-line venetoclax-based therapy, 15 had received GV as 1st-line treatment while 11 had received RV; none had received GIV as 1st-line treatment. The majority received acalabrutinib + venetoclax (AV, n=24); 2 received AV + obinutuzumab as 2nd-line treatment. The 2-year TFS2 rate was 21.4% for CIT, 76.6% for BTK inhibitor-based, 90.5% for venetoclax-based, and 88.5% for venetoclax + BTK inhibitor as 2nd-line treatment. The 2-year OS2 rate was 60% for CIT, 91.3% for BTK inhibitor-based, 100% for venetoclax-based and 92.4% for venetoclax + BTK inhibitor as 2nd-line treatment. Focusing on the 112 patients who had received venetoclax-based 1st-line treatment, the 2-year TFS2 after CIT, BTK inhibitor-based, venetoclax-based and venetoclax + BTK inhibitor as 2nd-line treatment was 27.8%, 77.9%, 81.4% and 100%, respectively. Conclusion: To our knowledge, we here report on the largest cohort of patients receiving 2nd-line treatment after venetoclax-based 1st-line treatment. With 2nd-line treatment choice at the discretion of the treating physician and focusing on patients with relapse within the first years, venetoclax-based retreatment for patients with TP53 wildtype CLL progressing after venetoclax-based 1st-line treatment is feasible, achieving 2-year TFS2 rates above 80%.