TP53 mutations are linked to unfavourable prognosis in chronic lymphocytic leukaemia

Dr Consuelo Bertossi - University Hospital of Ulm, Ulm, Germany

Our study concentrates on the TP53 mutation landscape in chronic lymphocytic leukaemia and its prognostic impact. It’s a multicentric retrospective analysis that included more than 10,000 CLL patients from our single institution and from 39 prospective clinical trials in order really to investigate how TP53 and all its intrinsic variables can affect prognostic impact in CLL, also in respect to other genetic markers and the kind of therapy that patients received.

It's really a translational research project that aimed to bring all the genetic results that we could get at our single institution academic facility in Ulm from the bench to the bedside.

What was the study design?

We selected these 10,051 CLL patients, two thirds of them were sequenced for TP53 via Sanger sequencing and DHPLC and one third via next generation sequencing. Afterwards we really planned to, and we did, perform a pathogenicity prediction and a variant interpretation following the current guidelines of the European Research Initiative for CLL that have been published on leukaemia in 2024 and also based on the UMD-based tool Seshat, an informatic tool for correct TP53 assessment.

Thanks to these informatic tools and to the guidelines, we could actually interpret TP53 with regards to its pathogenicity, the TP53 activity, its location inside and outside the DNA binding domain, they get loss of function and also the variant allele fraction.

Can you elaborate on the results of this study?

First of all, we could confirm in our efficacy cohort of previously untreated patients, 3,713 patients that we selected to correlate the genetic findings to the clinical result, we could confirm in this huge population that TP53 mutations are prognostic for PFS and OS and that they are standalone prognosticators in CLL. In fact, we also looked at mutated TP53 in the absence of a 17p deletion and we could confirm that even as an independent prognostic factor it had a significant impact on PFS and OS. Then we also looked at TP53 in unmutated and mutated IGHV status and in both cases it could retain its prognostic significance.

What is also very interesting and curious about our analysis is that we really looked at TP53 intrinsic and specific parameters and correlated them with outcome. What we found is, for example, that variants leading to a partially active TP53 do not really have an influence on PFS and OS and show a survival curve that is similar to wildtype. This is a finding that has been scarcely, if at all, described in CLL patients. We have some data regarding mouse models for solid oncology but not yet in CLL patients. So this was surprising, for example, as a result.