Ibrutinib for early-stage CLL: genetic risk factors and treatment outcome in the GCLLSG CLL12 trial.

Watch-and-wait is standard of care in asymptomatic early-stage chronic lymphocytic leukemia (CLL). The CLL12 trial investigated ibrutinib vs placebo for patients with early-stage CLL with intermediate to very high risk of progression, improving event-free survival (EFS) but not overall survival (OS). Building on these findings, our analysis examined whether a benefit could be identified within distinct genetic subgroups. After a median follow-up of 69.3 months, there were 166 EFS and 32 OS events in 515 trial patients. In the placebo arm, del(17p), del(11q), +12, unmutated immunoglobulin heavy variable chain (U-IGHV), and mutations in NOTCH1, ATM, NRAS/KRAS/BRAF, and NFKBIE correlated with shorter EFS. With ibrutinib, only del(17p) and TP53 and NFKBIE mutations significantly compromised EFS. Ibrutinib offered substantial EFS benefit in subgroups with U-IGHV, del(11q), +12, NOTCH1, ATM, and NFKBIE mutations. No EFS improvement was seen for patients with asymptomatic early-stage CLL with del(17p) or TP53 mutations. Ibrutinib provided no OS benefits in any genetic subgroup. Multivariable analysis revealed ibrutinib treatment as independent favorable factor for EFS, whereas U-IGHV, del(17p), POT1, RAS/RAF, and NFKBIE mutations were adverse prognostic factors. Results confirm watch-and-wait as standard of care for patients with early-stage CLL, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. This trial was registered at the European Union Drug Regulating Authorities Clinical Trials Database (2013-003211-22).