SOMATIC TP53 mutations are common in cancers, affecting progression and treatment resistance. In chronic lymphocytic leukaemia (CLL), these mutations lead to poor treatment responses and lower survival rates. The prognostic significance of different mutations, their clonal size, and coexistence with other genetic alterations under various therapies remains unclear. This study examined the TP53 mutation landscape in CLL and its prognostic impact across clinical trials, considering genetic risk factors and treatments.
DNA sequencing of 10,051 patients from 39 clinical trials and a single centre was performed using Sanger or Next Generation Sequencing with detection limits of 5% and 2%, respectively. Mutations were classified using the UMD database Seshat. Genetic aberrations and IGHV status were available in 94% and 99% of TP53-mutated cases. Outcome correlations involved 3,713 untreated patients from various GCLLSG trials.
At a median follow-up of 65.7 months, patients with TP53 mutations had worse progression-free survival (PFS, HR: 2.1, p<0.001) and overall survival (OS, HR: 2.8, p<0.001) compared to those with wildtype TP53. This negative impact was seen in both DNA binding and non-binding domain mutations. All types of TP53 mutations, including gain/loss of function, splice site, nonsense, and pathogenic missense mutations, were linked to shorter survival, while missense variants of unknown significance and partial p53 activity mutations did not affect prognosis.
Minor TP53 mutations (variant allele fraction <10%) were linked to shorter overall survival (HR: 1.8, p=0.020) but not progression-free survival. The number of TP53 variants affected survival only without del(17p); two mutations resulted in worse outcomes (PFS, HR:3.7, p<0.001; OS, HR:4.4, p<0.001) than one. Patients with del(17p) and unmutated TP53 had poor PFS but longer OS than those with both deletion and mutation.
Unmutated IGHV was linked to shorter PFS and OS in both TP53 wildtype (PFS HR: 2.1, OS HR: 2.0, p<0.001) and mutated cases (PFS, HR: 1.6, p<0.010; OS, HR: 2.2, p<0.001). TP53 mutations resulted in shorter PFS and OS with higher hazard ratios under chemoimmunotherapy (PFS HR: 2.6; OS, HR: 3.0, p<0.001) than targeted treatments (PFS, HR: 1.6, p=0.01; OS, HR: 2.5, p<0.01). TP53 mutations did not significantly affect PFS (HR: 1.5, p=0.210) or OS (HR: 2.6, p=0.080) under ibrutinib-based regimens.
The study thus highlights the critical role of TP53 mutations in CLL, emphasising their prognostic significance and impact on different therapies and risk factors.
Reference
Consuelo B. The landscape of TP53 mutations and their prognostic impact in chronic lymphocytic leukemia. Abstract S101. EHA, 13 –16 June, 2024.
