TP53 Mutations Have Strong Prognostic Value for PFS and OS Outcomes in CLL

Consuelo Bertossi, MD

TP53 alterations can serve as an independent prognostic marker for progression-free survival (PFS) and overall survival (OS) outcomes among patients with chronic lymphocytic leukemia (CLL) who have received chemoimmunotherapy or targeted therapy regimens, according to Consuelo Bertossi, MD.¹

Results from a retrospective study evaluating the prognostic impact of TP53 mutations in CLL were presented at the 2024 EHA Congress. At a median follow-up of 65.7 months, patients with TP53 mutations (n = 1368) experienced significantly worse PFS (HR, 2.605; 95% CI, 1.804-2.365; P < .001) and OS (HR, 2.819; 95% CI, 2.377-3.344; P < .001) outcomes vs patients with TP53 wild-type disease (n = 8683). Moreover, TP53 mutation types, such as gain/loss of function, splice site, nonsense mutations, and pathogenic missense mutations, significantly affected PFS and OS. Minor TP53 mutations were associated with worse OS (HR, 1.78; P = .039) but not PFS (HR, 1.39; P = .076) outcomes vs wild-type TP53.

Additionally, the presence of 17p deletions with unmutated TP53 was also associated with poor PFS but improved OS. However, unmutated IGHV status remained a poor prognostic factor regardless of TP53 mutation status. Notably, patients with TP53 mutations (n = 237) experienced worse PFS and OS outcomes with chemoimmunotherapy and targeted therapies vs those with wild-type disease (n = 2403), although survival was shorter with chemoimmunotherapy vs venetoclax (Venclexta) in the TP53-mutated group.

“We demonstrated that mutated TP53 is a standalone prognostic parameter, and it remains valid as a prognosticator for PFS and OS in the absence of a 17p deletion [or IGHV mutation],” Bertossi stated during an interview with OncLive^®.

In the interview, Bertossi explained the prevalence and significance of TP53 alterations in CLL; described translational findings from a multicentric retrospective study highlighting the landscape of TP53 mutations; and detailed how TP53-specific parameters, IGHV mutation status, and treatment modality impacted its prognostic value for survival outcomes.

Bertossi is an assistant doctor in the Division of CLL in the Department of Internal Medicine III at Ulm University Hospital in Germany.

OncLive: What is the significance of TP53 alterations in CLL, and what do current data indicate about their potential prognostic value?

Bertossi:TP53 is the most frequently altered gene in human cancers. The prevalence of these mutations can range from 5% to 50% of several histologies and is particularly prevalent in CLL. TP53 disruptions can happen due to several mechanisms: the deletion of the TP53 locus on the short arm of chromosome 17 [17p], direct somatic TP53 mutations, and the combination of both. In CLL, we see a combination of both 17p deletions and TP53 mutations in approximately 60% of cases. In approximately 10% of patients, we see the TP53 mutation [alone].

The relevance [of this target] has been made clear in the era of chemotherapy and targeted therapy through current literature [showing] how TP53 disruptions affect PFS and OS. An example in the chemotherapy era may be the [phase 3] CLL8 trial [NCT00281918] that showed how mutated TP53 is an independent and strong prognostic factor in CLL through multivariable analysis. Additionally, for the intraclass-based regimens, the [phase 3] CLL14 trial [NCT02242942] also conducted a multivariable analysis [showing] how mutated TP53 can independently affect survival. Overall, TP53 mutation status due to deletion 17p or a somatic mutation is relevant in CLL.

What knowledge gaps did this multicentric retrospective analysis of TP53 mutations in CLL aim to address?

Our multicentric analysis was retrospective and focused on translational research. We were not aiming to show whether 1 targeted agent is superior to another; [instead], we wanted to bring genetic results with TP53 mutations from the bench to the bedside. First, we [conducted] a descriptive analysis [to] describe the landscape of TP53 [mutations]. We enrolled 10,051 patients with CLL from prospective clinical trials, so [there was] a certain degree of data accuracy. We also wanted to look at how TP53 mutations correlate with other genetic parameters that are known to affect survival and prognosis in CLL, such as deletion 17p or IGHV mutations.

To summarize, the description of the landscape and the correlation of TP53 with other genetic markers was crucial to our analysis and was one of our primary aims. To do that, we had to [leverage] a vast landscape and study population.

What methods were used to identify and classify TP53 mutations in this study population?

We included patients from 39 clinical trials. A total of 66% of the patients were sequenced for TP53 via Sanger sequencing and dHPLC, and 33% of the patients [were sequenced] via next-generation sequencing. Of course, a thorny issue was also the interpretation of the TP53 data. We based [this] on current guidelines from the European Research Initiative of CLL that were published in 2024. [Mutations were classified via the] UMD TP53 database tool Seshat, [which is] able to predict pathogenicity and resulting TP53 mutation activity.

What did this study reveal about the prevalence and prognostic role of TP53 mutations in CLL? How did these mutations correlate with other genetic markers and outcomes?

We found a TP53 mutation in 1368 out of 10,051 patients, [which translates to] a prevalence of approximately 13%. Then we investigated how TP53-intrinsic and -specific parameters correlated with outcomes. First, we assessed the predictive pathogenicity mutations and found that variants of unclear significance do not affect PFS and OS and therefore should not be considered [an effect of] TP53 mutations.

Then we looked at TP53 activity, which also provided some insight on the role of partially active TP53. That did not seem to be different from [the role of] wild-type TP53. This is a finding that, to my knowledge, had not been [demonstrated] yet in CLL [and has only been observed] in lung and breast cancer mouse models.

Then we investigated specific details of TP53 with respect to variant allele fraction, pathogenicity, activity, localization inside the DNA binding domain, and gain and loss of function of the mutation. Then we correlated TP53 mutations with all cytogenetic aberrations that were relevant in the prospective clinical trials we included. [These comprised] deletion 17p, deletion 11q, 13q, the trisomy 12 mutation, and IGHV status. [Overall], we confirmed that TP53 mutations are an independent prognostic marker that remains valid for both IGHV-mutated and -unmutated cells.

How did the prognostic value of mutated TP53 vary according to whether patients received chemoimmunotherapy or targeted, time-limited therapies?

Our analysis was translational, so it’s not suitable for making comparisons. Most patients received chemoimmunotherapy because we recruited [patients who had received treatment] between 1998 and 2023. Our priority was to have a vast population and describe all facets of TP53 mutations. A total of 71% [of patients] received chemoimmunotherapy, 19% [of patients received] venetoclax, and 10% [of patients received] time-limited ibrutinib [Imbruvica].

[In those treated with] chemoimmunotherapy, [mutated] TP53 was a valid prognosticator. That was also true with venetoclax-based regimens; we confirmed that venetoclax-based therapies cannot overcome the prognostic significance of mutated TP53. With time-limited ibrutinib, we saw a numerical difference in PFS and OS. However, this was not statistically significant in our cohort, with the caveats that the observation time was approximately 40 months in this cohort instead of the 65.7-month [observation time for the rest of the cohort, and that we had fewer events.

What additional data and future analyses are needed to better understand the behavior of mutated TP53 in CLL?

To describe how mutated TP53 behaves [in patients undergoing treatment with] continuous ibrutinib-based therapies, need to wait for [results from] the [phase 3] CLL17 clinical trial [NCT04608318]. We also need head-to-head comparisons between [agents such as] venetoclax and obinutuzumab [Gazyva].

In the future, we would like to perform a longitudinal analysis to see how our TP53-mutated clones evolved. In our analysis, we only included [previously] untreated patients. We would like to look at TP53 mutations after therapy and the effects of their dynamic in CLL.

Why are centralized academic reference diagnostics and biobanking important for conducting prospective clinical trials involving genetic analyses?

[Ultimately,] I want to underline the importance and the relevance of a single-center, academic diagnostic facility in prospective clinical trials. Our analysis was possible only because all genetic analyses were performed in [a single academic institution]. [This enabled us to] have control of the data, [ensure] data accuracy, and standardize [genetic] assessment [across study sites].

Reference

Bertossi C, Robrecht S, Ligtvoet R, et al. The landscape of TP53 mutations and their prognostic impact in chronic lymphocytic leukemia. Presented at: 2024 EHA Congress; Madrid, Spain; June 13-16, 2024. Abstract S101.