The landscape of TP53 mutations and their prognostic impact in CLL

A comprehensive study into the role of TP53 mutations in chronic lymphocytic leukaemia (CLL) revealed various clinical implications of TP53 mutations and their prognostic value for targeted therapies.

Dr Consuelo Bertossi (University Hospital Ulm, Germany) and colleagues investigated the prognostic impact of TP53 mutations in CLL in the context of other genetic markers and different treatment regimens [1]. For this purpose, they analysed the expression patterns of tumour cells of 10,051 participants with CLL through denaturing high-performance liquid chromatography, Sanger sequencing, next-generation sequencing, and variant interpretation according to ERIC guidelines and Seshat.

Of the total study population, 1,368 participants had TP53 mutations. Overall, 1,824 TP53 variants were detected, of which 1,273 (69.8%) were missense mutations, 244 (13.4%) were of the frameshift type, 131 (7.2%) were nonsense mutations, 125 (6.9%) were splice site mutations, 20 (1%) were classified as synonymous mutations, and 31 (1.7%) were categorised as ‘other’. The same distribution and number of mutations were reported for participants with or without del(17p). However, it was noted that del(17p) was associated with higher variant allele frequency (44% vs 20%; P<0.001).

The efficacy cohort of the study included 3,713 participants from 9 different clinical trials, of whom 9% had TP53 mutations. Participants with TP53 mutations had worse progression-free survival (HR 2.61; 95% CI 1.80–2.37; P<0.001) and overall survival (HR 2.82; 95% CI 2.38–3.34; P<0.001) outcomes than those with TP53 wild-type disease. Dr Bertossi added that both minor (variant allele frequency <10%) and major TP53 mutations negatively impacted progression-free and overall survival, whereby the impact of major mutations appeared to be more pronounced.

“We also noted that pathogenic, deleterious, and truncating TP53 mutations affected overall survival outcomes, whereas variant of uncertain significance mutations associated with similar outcomes as observed for TP53 wild-type disease,” according to Dr Bertossi. Furthermore, the prognostic impact of TP53 mutations was independent of del(17p) and immunoglobulin heavy chain gene (IGHV) status. Finally, all participants displayed improved survival outcomes with venetoclax or ibrutinib compared with chemo-immunotherapy; those with wild-type disease had better outcomes than those with mutated disease, irrespective of administered therapy.

1. Bertossi C, et al. The landscape of TP53 mutations and their prognostic impact in chronic lymphocytic leukemia. S101, EHA congress 2024, 13–16 June, Madrid, Spain.

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Posted on 12 August 2024