The CLL12 trial: Genetic risk factors and outcomes with ibrutinib in early-stage CLL

Results from an analysis of the randomized, double-blind, placebo-controlled phase III CLL12 trial (EudraCT 2013-003211-22), which investigated the prognostic impact of genetic risk factors on ibrutinib treatment outcomes in 515 patients with asymptomatic early-stage chronic lymphocytic leukemia (CLL), were published in Blood by Riecke et al. The primary endpoint was event-free survival (EFS).

Key data: At a median follow-up of 69.3 months, there were a total of 166 EFS events and 32 overall survival (OS) events. In the placebo arm, negative prognostic factors for EFS included del(17p) (p = 0.026), del(11q) (p < 0.001), trisomy 12 (p = 0.048), unmutated immunoglobulin heavy variable chain (U-IGHV; p < 0.001), and ATM (p = 0.001), NOTCH1 (p = 0.002), NRAS/KRAS/BRAF (p = 0.001), and NFKBIE (p < 0.001) mutations. Ibrutinib significantly improved EFS vs placebo in patients with U-IGHV (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.29–0.9; p = 0.02), del(11q) (HR, 0.1; 95% CI, 0.04–0.29; p < 0.001), or trisomy 12 (HR, 0.33; 95% CI, 0.12–0.91; p = 0.031), as well as in patients with ATM (HR, 0.12; 95% CI, 0.03–0.43; p = 0.001), NOTCH1 (HR, 0.19; 95% CI, 0.06–0.55; p = 0.003), or NFKBIE (HR, 0.15; 95% CI, 0.04–0.53; p = 0.003) mutations. No EFS benefit was observed with ibrutinib in patients with del(17p) or mutated TP53. Ibrutinib provided no OS benefit in any genetic subgroup vs placebo. 

Key learning: Results indicate that watch-and-wait remains the standard of care for patients with asymptomatic early-stage CLL, regardless of genetic risk category, including those with high-risk features such as del(17p) and/or mutated TP53.