Data from Clinical Outcomes in Patients with Multi-Hit <i>TP53</i> Chronic Lymphocytic Leukemia Treated with Ibrutinib

Abstract

<div>AbstractPurpose:<p><i>TP53</i> aberration (<i>TP53</i> mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each <i>TP53</i> aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) <i>TP53</i> aberrations remains unclear, particularly in the context of targeted agents.</p>Patients and Methods:<p>We performed deep sequencing of <i>TP53</i> using baseline samples collected from 51 <i>TP53</i> aberrant patients treated with ibrutinib in a phase II study (NCT01500733).</p>Results:<p>We identified <i>TP53</i> mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit <i>TP53</i>, respectively. The multi-hit <i>TP53</i> 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 <i>TP53</i> compared with those with single-hit <i>TP53</i>. Clinical outcomes were similar in patient subgroups stratified by 2 or >2 <i>TP53</i> aberrations. In multivariable analyses, multi-hit <i>TP53</i> 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.</p>Conclusions:<p>In this study, single-hit <i>TP53</i> defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit <i>TP5</i>3 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit <i>TP53</i> CLL.</p><p><i>See related commentary by Bomben et al., p. 4462</i></p></div>