Clinical impact of TP53 disruption in chronic lymphocytic leukemia patients treated with ibrutinib: a campus CLL study

Disruption of the TP53 gene, through deletion at chromosome 17p13.1 (del17p) or mutations, is a critical prognostic factor in chronic lymphocytic leukemia (CLL), particularly in the context of novel targeted therapies like ibrutinib. While TP53 deletions and mutations often co-occur and are viewed as similar prognostic markers, the clinical implications of isolated or concomitant mutations and deletions remain unclear. This retrospective multicenter study, conducted as part of the “Campus CLL” initiative, investigates the impact of TP53 mutations and del17p in CLL patients treated with ibrutinib. A cohort of 229 CLL patients, including 51 treatment-naïve and 178 refractory/relapsed patients, were analyzed. TP53 mutation analysis utilized an ultra-deep next-generation sequencing (NGS) approach, covering exons 2–11, with a minimum coverage of 2,000X to ensure high sensitivity. Del17p and 11q22.3 deletions were detected using interphase FISH. Median follow-up was 36.3 months (95% CI 29.5–41.5), and clinical outcomes, including overall survival (OS) and progression-free survival (PFS), were evaluated. The results show that CLL patients with del17p had significantly poorer OS and PFS compared to those without del17p. A total of 296 TP53 mutations were detected in 126 patients (55%), with VAF ranging from 0.53% to 95.24%. Low- and high-VAF TP53 mutations were associated with shorter OS, reinforcing the negative prognostic impact of TP53 disruption, even at low mutation burdens. Multivariable analysis confirmed that TP53 mutations, particularly those with high VAF, were significant predictors of poorer OS and PFS. These findings highlight the clinical relevance of TP53 mutations and del17p in CLL treatment with ibrutinib, suggesting that even low-burden TP53 mutations may adversely affect patient outcomes and should be considered when assessing prognosis in clinical practice. Further validation of these results in larger prospective studies is needed to refine therapeutic strategies for TP53-disrupted CLL.