Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial

Clinical Snapshot

Key Findings

• P Value: GV vs CIT: P<0.001; GIV vs CIT: P<0.001; GV vs RV: P<0.001; GIV vs RV: P<0.001; GIV vs GV: P=0.0046; OS differences: not statistically significant

• Effect Size: Absolute PFS benefit at 5 years: GIV vs CIT ~30.6 percentage points; GV vs CIT ~19.1 percentage points; GIV vs GV ~11.5 percentage points. No statistically significant OS differences observed (5-year OS: GIV 94.3%, GV 93.6%, RV 94.7%, CIT 90.7%)

• Primary Outcome: 5-year progression-free survival: GIV 81.3%, GV 69.8%, RV 57.4%, CIT 50.7%. PFS superior for GV and GIV vs both CIT and RV (P<0.001 each); GIV superior to GV (P=0.0046)

• Nnt Or Sensitivity: Estimated NNT to prevent one progression event at 5 years: ~3 (GIV vs CIT, absolute risk reduction ~30.6%); ~5 (GV vs CIT, absolute risk reduction ~19.1%). Venetoclax re-treatment after venetoclax-based first-line: 2-year treatment-free survival >80% from second-line treatment initiation

• Confidence Interval: Full hazard ratios with 95% confidence intervals not reported in abstract; p-values indicate high statistical precision for primary PFS comparisons (P<0.001 for GV/GIV vs CIT/RV; P=0.0046 for GIV vs GV)

Abstract

Fixed-duration venetoclax combinations have become a standard first-line treatment in chronic lymphocytic leukemia (CLL). The phase 3 CLL13/GAIA trial assesses 3 time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV), in comparison with chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between 6 cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR] or bendamustine-rituximab [BR]) or 12 cycles of RV, GV, or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease at months 12/15). In total, 926 patients were randomized (GIV: 231, GV: 229, RV: 237, and CIT: 229 [FCR: 150, BR: 79]). With a median observation time of 63.8 months, 5-year progression-free survival (PFS) rates were 81.3% (GIV), 69.8% (GV), 57.4% (RV), and 50.7% (CIT). PFS was superior for GV and GIV compared with CIT and RV (P< .001 in each case). In addition, GIV showed longer PFS than GV (P = .0046). Venetoclax-based re-treatment after venetoclax-based first-line regimens was efficacious, with 2-year treatment-free survival >80% from second-line treatment. No differences in overall survival were observed between treatment arms (5-year rates: GIV, 94.3%; GV, 93.6%; RV, 94.7%; and CIT, 90.7%). The incidence rates of severe infections were highest with CIT, whereas cardiac events were most frequent with GIV. Compared with patients treated with CIT, those treated with GV or RV reported rapid and significantly greater quality-of-life (QoL) improvements. In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. This trial was registered at www.clinicaltrials.gov as NCT02950051.