Clinical Outcomes in Patients with Multi-Hit TP53 Chronic Lymphocytic Leukemia Treated with Ibrutinib

Abstract

Purpose: TP53 aberration (TP53 mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each TP53 aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) TP53 aberrations remains unclear, particularly in the context of targeted agents.

Patients and methods: We performed deep sequencing of TP53 using baseline samples collected from 51 TP53 aberrant patients treated with ibrutinib in a phase II study (NCT01500733).

Results: We identified TP53 mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit TP53, respectively. The multi-hit TP53 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 TP53 compared with those with single-hit TP53. Clinical outcomes were similar in patient subgroups stratified by 2 or >2 TP53 aberrations. In multivariable analyses, multi-hit TP53 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 TP53 defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit TP53 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit TP53 CLL.See related commentary by Bomben et al., p. 4462.

Figure 1.

Characterization of TP53 mutations. (A) Overall, 220 mutations were identified: 43 high burden [variant allele frequency (VAF) >10%] and 177 low burden mutations (VAF ≤10%) including 146 minor mutations (VAF <1%). (B) Mutations were mainly identified in hot spot exons 5–9. (C) In all 51 patients, 17p deletion [del(17p); red] and TP53 mutations (blue) mainly cooccurred (purple). (D) Patients were grouped into single-hit and multi-hit TP53 aberrations.

Figure 2.

(A, C) Overall survival and (B, D) progression-free survival following initiation of single-agent ibrutinib stratified on (A-B) single-hit (gray) vs. multi-hit (black striped) TP53 and in (C-D) patients carrying 1 (gray) vs. 2 (dark gray striped) vs. > 2 (black striped) TP53 aberrations. Overall survival and progression-free survival were significantly shorter in patients with multi-hit TP53. However, stratifying multi-hit TP53 patients further into carrying 2 and > 2 TP53 aberrations demonstrated similar outcome.

Figure 3.

Multivariable analyses with Firth’s penalized likelihood. (A) No baseline risk factors demonstrated impact on overall survival (OS), whereas (B) multi-hit TP53 and prior therapy were independently associated with shorter progression-free survival (PFS). Abbreviations: B2M, β2-microglobulin; U-CLL, unmutated immunoglobulin heavy-chain variable region gene (IGHV) status.

Figure 4.

Validation of multi-hit TP53 in 112 TP53 aberrant patients with chronic lymphocytic leukemia following initiation of single-agent ibrutinib. (A) Overall survival and (B) progression-free survival in patients with single-hit (gray) and multi-hit (black striped) TP53. Overall survival and progression-free survival were significantly shorter in patients with multi-hit TP53.