Clinical Outcomes in Patients with Multi-Hit Chronic Lymphocytic Leukemia Treated with Ibrutinib.

Purpose: aberration ( mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) aberrations remains unclear, particularly in the context of targeted agents.

Patients And Methods: We performed deep sequencing of using baseline samples collected from 51 aberrant patients treated with ibrutinib in a phase II study (NCT01500733).

Results: We identified mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit , respectively. The multi-hit subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit compared with those with single-hit . Clinical outcomes were similar in patient subgroups stratified by 2 or >2 aberrations. In multivariable analyses, multi-hit CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib.

Conclusions: In this study, single-hit defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit 3 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit CLL..