Ibrutinib in early stage CLL: Genetic risk factors and treatment outcome in the GCLLSG CLL12 trial

Watch & wait is the standard of care in asymptomatic early-stage chronic lymphocytic leukemia (CLL). The CLL12 trial investigated ibrutinib versus placebo in early-stage patients with intermediate to very high risk of progression, showing improved event-free survival (EFS) but no overall survival (OS) benefit10. Building on these findings, our analysis examined whether a significant 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, 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 asymptomatic early-stage patients with del(17p) or TP53 mutations. Ibrutinib provided no OS benefits in any genetic subgroup. Multivariable analysis revealed ibrutinib treatment as an independent favorable factor for EFS, while U-IGHV, del(17p), POT1, RAS/RAF, and NFKBIE mutations were adverse prognostic factors. The results confirm watch-and-wait as standard of care for early-stage CLL patients, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. EudraCT Number: 2013-003211-22