Efficacy of continuous ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia with high-burden and low-burden TP53 mutations: Multicenter retrospective analysis of the Polish Adult Leukemia Group (PALG)

BACKGROUND: TP53 gene aberrations, including deletions (del(17p)) and mutations, are the strongest predictors of shorter response duration and survival with most therapies for chronic lymphocytic leukemia (CLL). However, the impact of isolated TP53 mutations (without concomitant deletion of the 2nd allele) on outcomes of treatment with Bruton tyrosine kinase inhibitors remains less clear, especially in the context of low-burden mutations. OBJECTIVES: This retrospective analysis aimed to assess the efficacy of ibrutinib in patients with relapsed/refractory CLL and TP53 mutations. MATERIAL AND METHODS: Patients were selected from a large observational study conducted by the Polish Adult Leukemia Group (PALG) based on the following criteria: the presence of a lowor high-burden TP53 mutation detected by next-generation sequencing (NGS), the absence of del(17p), and treatment with ibrutinib. RESULTS: Of the 468 patients tested using NGS, isolated TP53 mutations were identified in 76 patients, 25 of whom received ibrutinib. This cohort included 13 patients with high-burden mutations (variant allele frequency (VAF) ≥10%) and 12 with low-burden mutations (VAF < 10%). After a median follow-up of 19 months (range: 1-40 months), the best overall response rate (ORR) in the entire study cohort was 84%, with a median progression-free survival (PFS) of 21 months and a median overall survival (OS) of 21 months. There were no statistically significant differences in PFS or OS between the highand low-burden groups (hazard ratio (HR) = 0.74 (95% confidence interval (95% CI): 0.28-2.01); p = 0.559 and HR = 0.75 (95% CI: 0.28-2.01), respectively). CONCLUSIONS: In patients with isolated TP53 mutations, the efficacy of ibrutinib did not appear to differ according to mutational burden.